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Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan–Meier method. Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets. [ABSTRACT FROM AUTHOR]

Taxanes are the best-known compounds in Taxus cuspidata owing to their strong anticancer effects. However, the traditional taxanes extraction method is the solid–liquid extraction method, which is limited by a large energy consumption and low yield. Therefore, it is urgent to find an efficient method for taxanes extraction. The ultrasonic microwave synergistic extraction (UME) method integrates the cavitation effect of ultrasound and the intensifying heat transfer (ionic conduction and dipole rotation of molecules) effect of microwave to accelerate the release of intracellular compounds and is used in active ingredient extractions. This study aimed to evaluate the performance of UME in extracting taxanes from T. cuspidata needles (dichloromethane-ethanol as extractant). A single-factor experiment, Plackett–Burman design, and the response surface method showed that the optimal UME parameters for taxanes extraction were an ultrasonic power of 300 W, a microwave power of 215 W, and 130 sieve meshes. Under these conditions, the taxanes yield was 570.32 μg/g, which increased by 13.41% and 41.63% compared with the ultrasound (US) and microwave (MW) treatments, respectively. The reasons for the differences in the taxanes yield were revealed by comparing the physicochemical properties of T. cuspidata residues after the UME, US, and MW treatments. The cell structures were significantly damaged after the UME treatment, and numerous tiny holes were observed on the surface. The absorption peaks of cellulose, hemicellulose, and lignin increased significantly in intensity, and the lowest peak temperature (307.40 °C), with a melting enthalpy of −5.19 J/g, was found after the UME treatment compared with the US and MW treatments. These results demonstrate that UME is an effective method (570.32 μg/g) to extract taxanes from T. cuspidata needles by destroying cellular structures. [ABSTRACT FROM AUTHOR]

Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in the improvement of patient outcome. In addition, DTX plus immune check inhibitors (ICIs) showed low toxicity and an increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulated data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings, including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, the development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms, such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects, such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding, the mechanisms of resistance may help in developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignant disease and the leading cause of mortality among women worldwide. Antineoplastic chemotherapy is one of its primary treatments, typically based on the class of drugs known as taxanes. Despite their proven therapeutic efficacy, these drugs can induce severe toxicities, leading to dose limitations or even treatment discontinuation. The objective of this study was to describe the clinical–epidemiological profile, risk factors, and toxicities of taxane-based chemotherapy treatment in women with breast cancer in the Amazon region. This is a cross-sectional, quantitative, and descriptive study conducted with 300 women diagnosed with breast cancer undergoing taxane treatment. Most patients were in the 40–49 age range, of brown ethnicity, and had completed elementary school. The majority of patients had risk factors such as alcoholism and a sedentary lifestyles. Most women had their first pregnancy between the ages of 18 and 21, breastfed their children, had menarche between the ages of 12 and 13, and were pre-menopausal and with a family history of cancer. The most frequent histological type was non-special invasive carcinoma and the Luminal B subtype. Most participants in this study showed taxane toxicity, with neurotoxicity being the most frequent. These findings reveal the importance of early detection, comprehensive risk factors, and effective management of treatment toxicities to improve patient outcomes in breast cancer care in the Amazon region. [ABSTRACT FROM AUTHOR]

Oncologic disease is a significant global health issue that causes thousands of deaths annually, and it has a significant impact on the quality of life of patients. Prostate cancer (PCa) is the second most diagnosed cancer and the fourth leading cause of cancer-related death in men in the Western world. Delineation of pathogenetic pathways and key driver molecular alterations involved in PCa development has provided a roadmap for the evaluation of biomarkers in predicting disease outcome and to identify potential therapeutic targets. Chemotherapeutic agents introduced from the 1990s include the taxanes (paclitaxel, docetaxel, and cabazitaxel), which are the anticancer drugs used most frequently for PCa treatment. This review presents the current knowledge about the onset and development of PCa, the state of the art of the use of taxane-based therapy, and their combination with targeting different transmembrane oncoproteins in PCa. The silencing of some transmembrane proteins can improve taxane sensitivity, and therefore may be a mechanism to improve the effectiveness of these drugs in PCa treatment. This combined therapy needs to be explored as a potential therapeutic agent for reducing cell proliferation, migration, and invasiveness in PCa. [ABSTRACT FROM AUTHOR]

The low distribution of hydrophobic anticancer drugs in patients is one of the biggest limitations during conventional chemotherapy. SDS-based polyelectrolyte multicore nanocarriers (NCs) prepared according to the layer by layer (LbL) procedure can release paclitaxel (PTX), and selectively kill cancer cells. Our main objective was to verify the antitumor properties of PTX-loaded NCs and to examine whether the drug encapsulated in these NCs retained its cytotoxic properties. The cytotoxicity of the prepared nanosystems was tested on MCF-7 and MDA-MB-231 tumour cells and the non-cancerous HMEC-1 cell line in vitro. Confocal microscopy, spectrophotometry, spectrofluorimetry, flow cytometry, and RT PCR techniques were used to define the typical hallmarks of apoptosis. It was demonstrated that PTX encapsulated in the tested NCs exhibited similar cytotoxicity to the free drug, especially in the triple negative breast cancer model. Moreover, SDS/PLL/PTX and SDS/PLL/PGA/PTX significantly reduced DNA synthesis. In addition, PTX-loaded NCs triggered apoptosis and upregulated the transcription of Bax, AIF, cytochrome-c, and caspase-3 mRNA. Our data demonstrate that these novel polyelectrolyte multicore NCs coated with PLL or PLL/PGA are good candidates for delivering PTX. Our discoveries have prominent implications for the possible choice of newly synthesized, SDS-based polyelectrolyte multicore NCs in different anticancer therapeutic applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial ovarian cancer remains the most fatal gynaecological malignancy, and cytoreductive surgery followed by adjuvant taxane-platinum-based chemotherapy remains the core therapy for women suffering from this cancer. The systemic inflammatory response plays a dual role in the pathophysiology of neoplastic diseases, activating the cytotoxic immune response against cancer cells and contributing to the progression of the disease via inflammatory mediators, including cytokines and growth factors. Increased systemic inflammatory markers at the time of cancer diagnosis are associated with advanced stage and tumour grade and predict poor survival; however, only a few studies have investigated changes in inflammatory markers during anti-cancer treatment in the context of clinical and pathological cancer features as well as applied therapies. In this study, we aimed to investigate the trends in changes in inflammatory markers in women with ovarian cancer receiving standard first-line adjuvant chemotherapy and identify the potential factors influencing these changes. Background: Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy treated with cytoreductive surgery followed by adjuvant taxane-platinum-based chemotherapy. It has been shown that the pretreatment systemic inflammatory reaction (SIR) in women with OC can be evaluated using the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory index (SII), depending on the stage of disease, and has prognostic value for overall survival. The aim of this study was to evaluate the changes in NLR, LMR, PLR and SII during chemotherapy. Methods: A total of 107 women with EOC (23 with type I and 84 with type II tumours) were included in a retrospective single-centre analysis. The Kologomorov−Smirnoff, Kruskal-Wallis or Friedman analysis of variance tests were used for data analysis, and a p value of 0.05 was considered statistically significant. Results: A significant decrease in NLR, PLR and SII but not LMR was observed during adjuvant treatment. Pretreatment NLR, PLR and SII were dependent on disease stage and tumour grade; however, this association was lost during therapy. Additionally, strong and positive mutual correlations between NLR, LMR, PLR and SII were sustained during the whole course of chemotherapy. Conclusions: During first-line adjuvant chemotherapy in women with EOC, a decrease in SIR is confirmed. [ABSTRACT FROM AUTHOR]

Taxus cell cultures are a reliable biotechnological source of the anticancer drug paclitaxel. However, the interplay between taxane production and other metabolic pathways during elicitation remains poorly understood. In this study, we combined untargeted metabolomics and elicited Taxus baccata cell cultures to investigate variations in taxane-associated metabolism under the influence of 1 µM coronatine (COR) and 150 µM salicylic acid (SA). Our results demonstrated pleiotropic effects induced by both COR and SA elicitors, leading to differential changes in cell growth, taxane content, and secondary metabolism. Metabolite annotation revealed significant effects on N-containing compounds, phenylpropanoids, and terpenoids. Multivariate analysis showed that the metabolomic profiles of control and COR-treated samples are closer to each other than to SA-elicited samples at different time points (8, 16, and 24 days). The highest level of paclitaxel content was detected on day 8 under SA elicitation, exhibiting a negative correlation with the biomarkers kauralexin A2 and taxusin. Our study provides valuable insights into the intricate metabolic changes associated with paclitaxel production, aiding its potential optimization through untargeted metabolomics and an evaluation of COR/SA elicitor effects. [ABSTRACT FROM AUTHOR]

Taxus spp. are ancient tree species that have survived from the Quaternary glacier period, and their metabolites, such as taxol, have been used as anticancer drugs globally. Plant–endophytic microbial interaction plays a crucial role in exerting a profound impact on host growth and secondary metabolite synthesis. In this study, high-throughput sequencing was employed to explore endophytic microbial diversity in the roots, stems, and leaves of the Taxus yunnanensis (T. yunnanensis). The analysis revealed some dominant genera of endophytic bacteria, such as Pseudomonas, Neorhizobium, Acidovorax, and Flavobacterium, with Cladosporium, Phyllosticta, Fusarium, and Codinaeopsis as prominent endophytic fungi genera. We isolated 108 endophytic bacteria and 27 endophytic fungi from roots, stems, and leaves. In vitro assays were utilized to screen for endophytic bacteria with growth-promoting capabilities, including IAA production, cellulase, siderophore production, protease and ACC deaminase activity, inorganic phosphate solubilization, and nitrogen fixation. Three promising strains, Kocuria sp. TRI2-1, Micromonospora sp. TSI4-1, and Sphingomonas sp. MG-2, were selected based on their superior growth-promotion characteristics. These strains exhibited preferable plant growth promotion when applied to Arabidopsis thaliana growth. Fermentation broths of these three strains were also found to significantly promote the accumulation of taxanes in T. yunnanensis stem cells, among which strain TSI4-1 demonstrated outstanding increase potentials, with an effective induction of taxol, baccatin III, and 10-DAB contents. After six days of treatment, the contents of these metabolites were 3.28 times, 2.23 times, and 2.17 times the initial amounts, reaching 8720, 331, and 371 ng/g of dry weight of stem cells, respectively. These findings present new insight into the industrialization of taxol production through Taxus stem cell fermentation, thereby promoting the conservation of wild Taxus resources by maximizing their potential economic benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: The study's purpose was to determine whether neurotoxic signs in breast cancer patients receiving taxane (paclitaxel) chemotherapy correlate with retinal or corneal nerve changes in a longitudinal study combining oncological examinations with advanced biophotonic imaging techniques. Recruited breast cancer patients underwent regular monitoring sessions including the clinical assessment of their quality of life and neurological scores, ophthalmological status, retinal optical coherence tomography, and large area confocal laser scanning microscopy of their corneal subbasal nerve plexus (SNP). The study revealed two key breakthroughs: an observable increase in retinal thickness and the examination of identical corneal SNP large-area mosaics over time. Consequently, advanced biophotonic imaging techniques could represent a powerful diagnostic tool for the objective assessment of the severity of adverse events, wherein oncologists and ophthalmologists could benefit from each other, leading to a better outcome for the patient. A common severe neurotoxic side effect of breast cancer (BC) therapy is chemotherapy-induced peripheral neuropathy (CIPN) and intervention is highly needed for the detection, prevention, and treatment of CIPN at an early stage. As the eye is susceptible to neurotoxic stimuli, the present study aims to determine whether CIPN signs in paclitaxel-treated BC patients correlate with ocular changes by applying advanced non-invasive biophotonic in vivo imaging. Patients (n = 14, 10 controls) underwent monitoring sessions after diagnosis, during, and after therapy (T0-T3). Monitoring sessions included general anamnesis, assessment of their quality of life, neurological scores, ophthalmological status, macular optical coherence tomography (OCT), and imaging of their subbasal nerve plexus (SNP) by large-area confocal laser-scanning microscopy (CLSM). At T0, no significant differences were detected between patients and controls. During treatment, patients' scores significantly changed while the greatest differences were found between T0 and T3. None of the patients developed severe CIPN but retinal thickenings could be detected. CLSM revealed large SNP mosaics with identical areas while corneal nerves remained stable. The study represents the first longitudinal study combining oncological examinations with advanced biophotonic imaging techniques, demonstrating a powerful tool for the objective assessment of the severity of neurotoxic events with ocular structures acting as potential biomarkers. [ABSTRACT FROM AUTHOR]

Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium Sorangium cellulosum. This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010–2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor Treating Fields (TTFields) are electric fields that prevent cancer cell survival and tumor growth, without impacting healthy cells. TTFields therapy is delivered to the tumor using arrays that are placed on the patient's skin, surrounding the tumor site, without the need for invasive procedures. Taxanes are chemotherapies used to successfully treat several aggressive cancers and are associated with side effects such as neutropenia (low neutrophils) and peripheral neuropathy. Although taxanes are considered to be the standard of care for many cancers, there is a need to identify other treatments that can be used in combination, to enhance their effectiveness, without increasing the side effects. The preclinical (laboratory) and clinical (human) data summarized here suggest that TTFields therapy together with taxanes may be beneficial in the treatment of several cancers. Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes; however, implementation is limited by additive toxicities and potential drug–drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patient's skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers. [ABSTRACT FROM AUTHOR]

Biologically active taxanes, present in small- to medium-sized evergreen conifers of various Taxus species, are widely used for their antioxidant, antimicrobial and anti-inflammatory effects, but mostly for their antitumour effects used in the treatment of solid tumours of the breast, ovary, lung, bladder, prostate, oesophagus and melanoma. More of the substances found in Taxus plant extracts have medical potential. Therefore, at the beginning of this review, we describe the methods of isolation, identification and determination of taxanes in different plant parts. One of the most important taxanes is paclitaxel, for which we summarize the pharmacokinetic parameters of its different formulations. We also describe toxicological risks during clinical therapy such as hypersensitivity, neurotoxicity, gastrointestinal, cardiovascular, haematological, skin and renal toxicity and toxicity to the respiratory system. Since the effect of the drug-form PTX is enhanced by various Taxus spp. extracts, we summarize published clinical intoxications and all fatal poisonings for the Taxus baccata plant. This showed that, despite their significant use in anticancer treatment, attention should also be focused on the risk of fatal intoxication due to ingestion of extracts from these plants, which are commonly found in our surroundings. [ABSTRACT FROM AUTHOR]

In the present study, an effective method of preparative high-performance liquid chromatography (Prep-HPLC) was established to purify two taxanes in Taxus cuspidata. During the experimental operation, the effects of flow rate, injection volume, and column temperature on the purity of 10-deacetyltaxol (10-DAT) and paclitaxel (PTX) were investigated, and the optimized conditions were as follows: flow rate of 10 mL/min, injection volume of 0.5 mL, and column temperature of 30 °C. Under these conditions, the purity of 10-DAT and PTX reached 95.33% and 99.15%, respectively. The purified products were characterized by scanning electron microscopy (SEM), high-performance liquid chromatography (HPLC), and electrospray ionization-high resolution mass spectrometry (ESI-HRMS). The results demonstrated that preparative HPLC can effectively purify 10-DAT and PTX from Taxus cuspidata with a purity of >95%, which was suitable for the large-scale preparation of 10-DAT and PTX. [ABSTRACT FROM AUTHOR]

Taxanes are natural compounds with strong antitumor activity. In this study, we first enriched taxanes by ultrasonic extraction and liquid–liquid extraction from Taxus cuspidata, then purified these taxanes by the antisolvent recrystallization method, and discussed the effects of four recrystallization conditions on the purity of eight target compounds. The most promising purification results were obtained using methanol as a solvent and water as an antisolvent. Response surface methodology (RSM) was used to further optimize the optimal purification conditions: when the crude extraction concentration was 555.28 mg/mL, an antisolvent to solvent volume ratio was 28.16 times, the deposition temperature was 22.91 °C, and the deposition time was 1.76 min, the purity of the taxanes reached its maximum. The scanning electron microscopy (SEM) results showed that recrystallization could effectively reduce the particle size of crude Taxus cuspidata and control the particle morphology. X-ray diffraction (XRD) and Raman spectrum experiments demonstrated that the amorphous state of the crude Taxus cuspidata did not change during the recrystallization process, and always remained amorphous. This recrystallization method can effectively improve the purity of taxanes in Taxus cuspidata, and is suitable for the preliminary purification of taxanes. [ABSTRACT FROM AUTHOR]

Fluoropyrimidine plus platinum (FP) and taxanes plus platinum (TP) are standard treatments for esophageal cancer (EC). This systematic review and meta-analysis aim to explore the difference in the therapeutic effect and toxicity of FP and TP regimens in EC patients. PubMed, Embase, and Cochrane were fully searched and analyzed to find relevant articles on EC patients treated with FP and TP regimens up to 22 March 2022. Thirty-one studies, with a total of 3432 participants, were included in this review. The primary outcomes showed that the prognosis and therapeutic efficacy of TP groups were better than those of FP groups for the EC patients treated with definitive chemoradiotherapy treatment (3-year OS: RR: 1.25, 95% CI: 1.08–1.44, p = 0.003; 3-year PFS: RR: 1.43, 95% CI: 1.17–1.75, p = 0.0006; ORR: RR: 1.17, 95% CI: 1.06–1.29, p = 0.001). However, TP therapy was significantly correlated with a higher incidence of leukopenia and thrombocytopenia (p < 0.05). In the preoperative neoadjuvant chemoradiotherapy group, these two groups had a similar survival time (p > 0.05). The FP regimen corresponded to a higher incidence of thrombocytopenia, while the TP regimen was associated with an increased incidence of febrile leukopenia (p < 0.05). Therefore, TP regimens could generate both superior clinical response and survival benefits when compared with FP regimens in EC patients undergoing definitive chemoradiotherapy. [ABSTRACT FROM AUTHOR]

The incidence of melanoma is steadily increasing worldwide. Melanoma is the most lethal skin cancer, and new therapeutic methods are being sought. Our research aimed to investigate the cytotoxic and antiproliferative effects of betulinic acid in vitro, used alone and in combination with taxanes (paclitaxel, docetaxel) in four melanoma cell lines. Isobolographic analysis allowed us to assess the interactions between these compounds. Betulinic acid had no cytotoxic effect on normal human keratinocyte HaCaT cells; the amount of LDH released by them was significantly lower compared to melanoma cell lines. The present study shows that betulinic acid significantly inhibits the growth of melanoma cell lines in vitro. The IC50 values of betulinic acid ranged from 2.21 µM to 15.94 µM against the four melanoma lines. Co-treatment of betulinic acid with paclitaxel or docetaxel generated desirable drug–drug interactions, such as an additive and additive with a tendency to synergy interactions. [ABSTRACT FROM AUTHOR]

Taxanes are natural compounds with strong antitumor activity. In this study, we first extracted taxanes from the needles of Taxus cuspidata using ultrasonic (US) extraction, and then assessed the effects of different extraction conditions on the yields of eight target compounds. Response surface methodology (RSM) was further used to optimize the extraction conditions: when the liquid-to-solid ratio was 20.88 times, ultrasonic power was 140.00 W, ultrasonic time was 47.63 min, and ethanol content in solvent was 83.50%, taxane yields reached the maximum value of 354.28 μg/g. Under these conditions, the actual extraction rate of taxanes from the needles was 342.27 μg/g. The scanning electron microscopy (SEM) results indicated that the morphology of the needles, suspension cells, and callus of Taxus cuspidata extracted by ultrasonic wave had changed, the pores of the sections of the needles extracted by ultrasonic wave had become relatively loose, and the pore diameter had obviously increased. The callus and overall structure of the suspension cells extracted by ultrasonic wave were destroyed, forming cell fragments. The components of Taxus cuspidata are complex; the high-performance liquid chromatography (HPLC) method established in this paper is suitable for the rapid and effective separation of taxanes in Taxus cuspidata. We systematically and comprehensively compared the yields of taxanes in needles, callus, and suspension cells of Taxus cuspidata, and the taxane yields were increased by the suspension cell culture. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinically observed sex differences in acute and long-term taxane chemotherapy-induced normal tissue toxicity are routinely documented but remain poorly understood despite the significant impact such toxicities have on treatment tolerance and quality of life outcomes in cancer survivors. This review draws from pre-clinical and clinical literature to highlight sex-specific mechanisms of action in taxane drug toxicity and proposes hypotheses for sex-specific clinical discrepancies in taxane-induced acute and long-term toxicities. To our knowledge, this is the first review exploring how sex as a biological variable impacts taxane-mediated mechanisms of action and clinical outcomes. In doing so, we have provided a novel framework to investigate and understand common sex differences observed in clinical and pre-clinical research. The taxane family of microtubule poisons and chemotherapeutics have been studied for over 50 years and are among the most frequently used antineoplastic agents today. Still, limited research exists characterizing taxane-induced sex-specific mechanisms of action and toxicities in cancer and non-cancerous tissue. Such research is important to advance cancer treatment outcomes as well as to address clinically observed sex-differences in short- and long-term taxane-induced toxicities that have disproportionate effects on female and male cancer patients. To gain more insight into these underlying differences between the sexes, the following review draws from pre-clinical and clinical paclitaxel and taxane oncology literature, examines sex-discrepancies, and highlights uncharacterized sex-dependent mechanisms of action and clinical outcomes. To our knowledge, this is the first literature review to provide a current overview of the basic and clinical sex dimorphisms of taxane-induced effects. Most importantly, we hope to provide a starting point for improving and advancing sex-specific personalized chemotherapy and cancer treatment strategies as well as to present a novel approach to review sex as a biological variable in basic and clinical biology. [ABSTRACT FROM AUTHOR]

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective observational study aims at highlighting the response to pertuzumab, trastuzumab and docetaxel treatment (THP), without using anthracycline, in patients with HER2-positive early breast cancer. We add evidence to the suitability of THP in real life to reach higher pathological complete response rates, with a good safety profile for patients. An exploratory analysis of the mutational status of PIK3CA was performed as well, and 21% mutated samples were identified, with overall higher pCR rates in PIK3CA mutant patients and, particularly, in those who were THP-treated. Our original results open the door to further studies focused on more in-depth analysis of the molecular and clinical features related to the response to anthracycline-free neoadjuvant treatment in HER2-positive early breast cancer patients. HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results. [ABSTRACT FROM AUTHOR]

Taxanes are a series of natural compounds with great application potential in antitumor therapy, whereas the lack of efficient taxanes extraction methods significantly hinders the development of taxanes. The high-intensity pulsed electric field (PEF) is a novel technology used to extract bioactive ingredients from food and other natural products. However, the prospect of using PEF for taxanes extraction remains to be elucidated. Herein, we extracted taxanes from Taxus cuspidata via PEF and explored the effects of seven extraction conditions on the yields of target compounds. The Placket–Burman design (PBD) assay revealed that electric field strength, pulse number, and particle size are key factors for taxanes extraction. The response surface methodology (RSM) and back-propagation neural network conjugated with genetic algorithm (GA-BP) were further used to model and predict the optimal extraction conditions, and GA-BP exerted higher reliability, leading to a maximum extraction yield of 672.13 μg/g under electric field strength of 16 kV/cm, pulse number of 8, particle size of 160 meshes, solid–liquid ratio of 1:60, a single extraction, centrifugal speed of 8000 r/min, and flow rate of 7 mL/min, which was 1.07–1.84 folds that of control, solid–liquid extraction (SL), and ultrasonic extraction (US) groups. Additionally, the scanning electron microscopy (SEM) results indicated that the sample particles extracted by PEF method exhibited a coarser surface morphology. Thus, we present for the first time that PEF is feasible for the extraction of taxanes from Taxus cuspidata and highlight the application value of the PBD, RSM, and GA-BP models in parameters optimization during extraction process. [ABSTRACT FROM AUTHOR]

Taxanes including paclitaxel and docetaxel are effective anticancer agents preferably sufficient for liposomal drug delivery. However, the encapsulation of these drugs with effective amounts into conventional liposomes is difficult due to their high hydrophobicity. Therefore, an effective encapsulation strategy for liposomal taxanes has been eagerly anticipated. In this study, the mixture of polyethoxylated castor oil (Cremophor EL) and ethanol containing phosphate buffered saline termed as CEP was employed as a solvent of the inner hydrophilic core of liposomes where taxanes should be incorporated. Docetaxel-, paclitaxel-, or 7-oxacetylglycosylated paclitaxel-encapsulating liposomes were successfully prepared with almost 100% of encapsulation efficiency and 29.9, 15.4, or 29.1 mol% of loading efficiency, respectively. We then applied the docetaxel-encapsulating liposomes for targeted drug delivery. Docetaxel-encapsulating liposomes were successfully developed HER2-targeted drug delivery by coupling HER2-specific binding peptide on liposome surface. The HER2-targeting liposomes exhibited HER2-specific internalization and enhanced anticancer activity in vitro. Therefore, we propose the sophisticated preparation of liposomal taxanes using CEP as a promising formulation for effective cancer therapies. [ABSTRACT FROM AUTHOR]

Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum-based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor-specific drug targets to tumor-specific determinants of drug uptake. [ABSTRACT FROM AUTHOR]

Taxanes are natural compounds for the treatment of lung cancer, but the molecular mechanism behind the effects is unclear. In the present study, through network pharmacology and molecular docking, the mechanism of the target and pathway of taxanes in the treatment of lung cancer was studied. The taxanes targets were determined by PubChem database, and an effective compounds-targets network was constructed. The GeneCards database was used to determine the disease targets of lung cancer, and the intersection of compound targets and disease targets was obtained. The Protein-Protein Interaction (PPI) network of the intersection targets was analyzed, and the PPI network was constructed by Cytoscape 3.6.0 software. The hub targets were screened according to the degree value, and the binding activity between taxanes and hub targets was verified by molecular docking. The results showed that eight taxane-active compounds and 444 corresponding targets were screened out, and 131 intersection targets were obtained after mapping with lung cancer disease targets. The hub targets obtained by PPI analysis were TP53, EGFR, and AKT1. Gene Ontology (GO) biological function enrichment analysis obtained 1795 biological process (BP) terms, 101 cellular component (CC) terms, and 164 molecular function (MF) terms. There were 179 signaling pathways obtained by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Twenty signaling pathways were screened out, mainly pathways in cancer, proteoglycans in cancer pathway, microRNAs in cancer pathway, and so on. Molecular docking shows that the binding energies of eight taxanes with TP53, EGFR, and AKT1 targets were less than -8.8 kcal/mol, taxanes acts on TP53, EGFR, and AKT1 targets through pathways in cancer, proteoglycans in cancer pathway and microRNAs in cancer pathway, and plays a role in treating lung cancer in biological functions such as protein binding, enzyme binding, and identical protein binding.

Although rapid advances in treatment options have improved the prognosis of advanced gastric cancer (AGC), it remains a major public health problem and the second leading cause of cancer-related deaths in the world. Taxanes (paclitaxel and docetaxel) are microtubule stabilizing agents that inhibit the process of cell division, and have shown antitumor activity in the treatment of AGC as a single or combination chemotherapy. Accordingly, this review focuses on the efficacy and tolerability of taxanes in the first- or second-line chemotherapy setting for AGC. [ABSTRACT FROM AUTHOR]

Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel. Methods: Increasing doses of fluvastatin, zoledronic acid, and paclitaxel were investigated as single agents and in combination, and synergistic interactions were evaluated by the Chou-Talalay method. Western blots were used to assess effects on signal transduction pathways. Results: Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 μM for fluvastatin and 5.35 ± 1.35 μM for zoledronic acid after 72 hours treatment. Geranylgeranyl pyrophosphate and farnesyl pyrophosphate was able to block, in part, this inhibitory activity. The combinations of zoledronic acid and paclitaxel, zoledronic acid and fluvastatin, and fluvastatin and paclitaxel were all synergistic. Both fluvastatin and zoledronic acid inhibited Ras and Rap prenylation, and the phosphorylation of ERK1/2 and AKT. The degree of inhibition of phosphorylation of these key signaling transduction pathways appears to closely correlate with their synergistic interactions. Conclusions: Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition. [ABSTRACT FROM AUTHOR]

A novel conjugate of docetaxel and biotin (designated as IDD-1010) was designed and chemically synthesized via an ester linkage at position 2' carbon in docetaxel. The synthesized pure IDD-1010 exhibits a potent anti-cancer activity in in vitro and in vivo studies. At 10 nM, IDD-1010 has induced increased apoptosis and mitotic arrest of PC3-Luc prostate cancer cells, causing aneuploidy and cell death at higher concentrations. Toxicology studies indicate that the maximal tolerated dose (MTD) of IDD-1010 is 150 mg/kg in mice; equivalent to about 12.2 mg/kg of body weight, or to about an 850 mg dose for a patient weighing 70 kg. The MTD-treated mice exhibited weight gain similar to that of the control group, with no gross pathological signs at 14 days post-dosing. At a lower dose, IDD-1010 treatment did not lead to any significant weight loss in mice, although decreased the tumor volume stemming from injecting cancer cells into the dorsal loop of mouse prostate, and it was found to be more potent than Paclitaxel (reference drug). Similarly, IDD-1010 treatment significantly reduced tumor weight and thereby increased the percentage of mice survival as compared to reference drug-treated and control groups. To summarize, the described experiments using IDD-1010, as compared to the reference drug, strongly suggest a potential treatment utility with a wider therapeutic window for prostate cancer. Henceforth, clinical research on such a novel drug candidate would be greatly worthwhile. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, a combination therapy of standard androgen deprivation therapy (ADT) plus docetaxel or androgen receptor-axis-targeted therapy is the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Compared to ADT monotherapy, combination treatment prolongs overall survival by at least 18 months. The latest data has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel. Ongoing clinical trials are investigating triple therapy protocols by affecting diverse signaling pathways that are pivotal in prostate cancer. In this review, we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future. For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or androgen receptor-axis-targeted therapy (ARAT) compared to ADT monotherapy. As a result, overall survival can be prolonged by at least 18 months. Recently published congress data of the PEACE-1 study suggests that in the future, triple therapy might be the new gold standard. In addition to this study, which has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel, several other phase III triple therapy studies are currently ongoing. The different modes of action that are investigated reach from AR-targeting over mitotic inhibition and immunotherapy to PARP and AKT inhibition. In this review we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future. [ABSTRACT FROM AUTHOR]

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies in tissue culture cell lines have indicated that silencing of the mitotic regulator CHFR is associated with increased paclitaxel sensitivity. More recently, it has been suggested that a UBC13-DNMT1-CHFR pathway also modulates sensitivity of ovarian cancer to paclitaxel in the clinic. Here we have credentialed an anti-CHFR monoclonal antibody for immunohistochemistry and directly examined the association of CHFR expression with outcome of paclitaxel-containing ovarian cancer therapy. While CHFR levels were higher in high grade, high stage ovarian cancer, after correction for stage and debulking status there was no association between CHFR levels and progression-free survival in high grade serous ovarian cancer treated with surgery followed by platinum/taxane therapy. Moreover, there was no association between CHFR expression and response of patient-derived ovarian cancer xenografts treated with paclitaxel monotherapy. These studies indicate that CHFR varies among ovarian cancers but is unlikely to be an independent biomarker for poor response to taxanes. The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an aggressive and chemoresistant cancer type. The development of novel therapeutic strategies is still urgently needed. Personalized or precision medicine is a new trend in cancer therapy, which treats cancer patients with specific genetic alterations. In this study, a gene signature was identified from the transcriptome of HCC patients, which was correlated with the patients' poorer prognoses. This gene signature is functionally related to mitotic cell cycle regulation, and its higher or lower expression is linked to the mutation in tumor protein p53 (TP53) or catenin beta 1 (CTNNB1), respectively. Gene–drug association analysis indicated that the taxanes, such as the clinically approved anticancer drug paclitaxel, are potential drugs targeting this mitotic gene signature. Accordingly, HCC cell lines harboring mutant TP53 or wild-type CTNNB1 genes are more sensitive to paclitaxel treatment. Therefore, our results imply that HCC patients with mutant TP53 or wild-type CTNNB1 genes may benefit from the paclitaxel therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer (PC) is a hormone-dependent disease in which metabolism deregulation has been identified as a relevant event. In particular, glutamine metabolism becomes crucial for biomass and energy production in PC cells. The main aim of this study was to determine whether the plasma glutamine levels correlated with clinical outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) receiving taxanes treatment. We retrospectively assessed the glutamine levels in plasma samples from 75 patients. As glutamine is a precursor of cholesterol production, we also assessed the cholesterol levels in the same cohort, plus 41 extra patients. We found that high glutamine plasma levels were associated with a shorter taxanes response and worse clinical outcome in patients with mCRPC. High cholesterol levels were also indicative of early progression. These results point out circulating glutamine and cholesterol levels as potentially prognostic biomarkers to be further explored in PC. Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients' clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression. [ABSTRACT FROM AUTHOR]

Simple Summary: The present study aimed to assess and compare the effects of receiving CAF (cyclophosphamide/doxorubicin/fluorouracil) and AC-T (doxorubicin/cyclophosphamide→taxanes) on exercise tolerance and cardiovascular responses in patients with early-stage breast cancer. We herein demonstrated that AC-T chemotherapy increased resting heart rate (RHR) and induced a greater reduction in exercise tolerance at the end of chemotherapy compared with CAF. Moreover, AC-T also lowered myocardial perfusion more than CAF, and it appeared that myocardial impairment occurred before the development of arterial stiffening after chemotherapy. We, therefore, suggest that AC-T chemotherapy might further limit the exercise capacity of patients with early-stage breast cancer. This study provides fundamental information regarding the variety of cardiovascular responses to exercise after chemotherapy in patients with early-stage breast cancer. This information will help clinical professionals in the fields of oncological and rehabilitation medicine to precisely prescribe post-chemotherapy exercise programs when patients are receiving different chemotherapies. Background: Adjuvant chemotherapies are commonly used for treating early-stage breast cancer. However, whether chemotherapeutic regimens affect exercise tolerance and cardiovascular responses remains unclear. Therefore, we investigated the effects of receiving CAF and AC-T on exercise tolerance and cardiovascular responses in patients with early-stage breast cancer. Methods: Thirty-four patients with breast cancer (age: 44 ± 1 years; stage I-II) received either CAF (n = 15) or AC-T (n = 19), depending on clinical decisions. Their step-exercise tolerance and cardiovascular responses were assessed before and after chemotherapy. Results: After chemotherapy, there were no differences in baseline measurements between patients receiving CAF or AC-T. The increases in resting heart rate (RHR) of those receiving AC-T was significantly greater than that of those receiving CAF. CAF and AC-T did not result in increased pulse wave velocity (PWV), yet the subendocardial viability ratio (SEVR) in patients receiving AC-T was significantly lower than the baseline. Greater change in post-exercise heart rate recovery (recovery HR) after chemotherapy was observed in those who had received AC-T; the Recovery HR in AC-T patients was significantly higher during post-exercise period than that in CAF patients. Conclusions: AC-T chemotherapy increases RHR and impairs exercise tolerance after chemotherapy more than CAF. Moreover, AC-T also lowers myocardial perfusion more than CAF after chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a clinical need for biomarkers predictive of resistance to taxane therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Based on existing evidence for the role of ATP-binding cassette (ABC) transporters in taxane resistance, we sought to assess the association between ABCB1 gene amplification and primary resistance to docetaxel or cabazitaxel in mCRPC patients using sparse whole genome sequencing from plasma-derived cell-free DNA (cfDNA). Because sparse whole genome sequencing is more cost-effective than traditional cfDNA profiling and less invasive than tissue biopsies, a clinically useful biomarker of taxane resistance discovered using this technique has the potential to be broadly applied in clinical practice. We did not detect a statistically significant association between ABCB1 amplification detected by this method and docetaxel or cabazitaxel resistance in our cohort. Future studies with larger samples including ABCB1 amplification in a suite of putative biomarkers are warranted to draw definitive conclusions. There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions. [ABSTRACT FROM AUTHOR]

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells are the target of most approved therapies. A growing body of evidence suggests that these agents have important roles in modulating the biology of host cells and their interactions with cancer cells, including blood vessels, fibroblasts, immune and fat cells, among others. This review provides an overview of potential roles of commonly used therapeutics in the tumor microenvironment, with a focus on cancer-associated fibroblasts. This includes an emphasis on therapies commonly used for the treatment of high-grade serous ovarian cancers (e.g., platinum, taxanes, PARP inhibitors, and anti-angiogenic agents). In vitro, in vivo, and clinical studies are included, and perspectives offered on how to best interpret the influence of therapeutics on normal cells. High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics. [ABSTRACT FROM AUTHOR]

Cognitive impairment is one of the most deleterious effects of chemotherapy treatment in cancer patients, and this problem sometimes remains even after chemotherapy ends. Common classes of chemotherapy-based regimens such as anthracyclines, taxanes, and platinum derivatives can induce both oxidative stress in the blood and in the brain, and these effects can be reproduced in neuronal and glia cell cultures. In rodent models, both the acute and repeated administration of doxorubicin or adriamycin (anthracyclines) or cisplatin impairs cognitive functions, as shown by their diminished performance in different learning and memory behavioural tasks. Administration of compounds with strong antioxidant effects such as N-acetylcysteine, gamma-glutamyl cysteine ethyl ester, polydatin, caffeic acid phenethyl ester, and 2-mercaptoethane sulfonate sodium (MESNA) counteract both oxidative stress and cognitive alterations induced by chemotherapeutic drugs. These antioxidant molecules provide the scientific basis to design clinical trials in patients with the aim of reducing the oxidative stress and cognitive alterations, among other probable central nervous system changes, elicited by chemotherapy in cancer patients. In particular, N-acetylcysteine and MESNA are currently used in clinical settings and are therefore attracting scientific attention. [ABSTRACT FROM AUTHOR]

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3 , CPS1 , and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or androgen receptor-axis-targeted therapy (ARAT) compared to ADT monotherapy. As a result, overall survival can be prolonged by at least 18 months. Recently published congress data of the PEACE-1 study suggests that in the future, triple therapy might be the new gold standard. In addition to this study, which has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel, several other phase III triple therapy studies are currently ongoing. The different modes of action that are investigated reach from AR-targeting over mitotic inhibition and immunotherapy to PARP and AKT inhibition. In this review we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future.

Thiomers (or thiolated polymers) have broken through as avant-garde approaches in anticancer therapy. Their distinguished reactivity and properties, closely linked to their final applications, justify the extensive research conducted on their preparation and use as smart drug-delivery systems (DDSs). Multiple studies have demonstrated that thiomer-rich nanoformulations can overcome major drawbacks found when administering diverse active pharmaceutical ingredients (APIs), especially in cancer therapy. This work focuses on providing a complete and concise review of the synthetic tools available to thiolate cationic and anionic polymers, in particular chitosan (CTS) and hyaluronic acid (HA), respectively, drawing attention to the most successful procedures. Their chemical reactivity and most relevant properties regarding their use in anticancer formulations are also discussed. In addition, a variety of NP formation procedures are outlined, as well as their use in cancer therapy, particularly for taxanes and siRNA. It is expected that the current work could clarify the main synthetic strategies available, with their scope and drawbacks, as well as provide some insight into thiomer chemistry. Therefore, this review can inspire new research strategies in the development of efficient formulations for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The X-linked inhibitor of apoptosis protein (XIAP) is considered the most potent inhibitor of cell death, and it is well established that XIAP promotes resistance to chemotherapy, radiation, and anti-cancer immune responses. This study evaluates the correlations between XIAP expression and clinicopathological features, including disease-free survival (DFS) and pathological complete response (pCR) to chemotherapy, in more than 2300 invasive primary breast cancer samples. We found a significant association of XIAP expression with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, and PAM50 luminal B subtype. Analysis of molecular subtypes revealed a stronger prognostic value in HR+/HER2− tumors. Higher XIAP expression was associated with shorter DFS and lower pCR rate to chemotherapy in both uni- and multivariate analyses. All these correlations were observed at both the RNA and protein level, indicating the potential of XIAP as a promising therapeutic target in primary invasive breast cancer. XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2− status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2− but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP. [ABSTRACT FROM AUTHOR]

The combination of nab-paclitaxel and gemcitabine demonstrated greater efficacy than gemcitabine alone but resulted in higher rates of chemotherapy-induced peripheral neuropathy (CINP) in patients with metastatic pancreatic cancer (mPC). We aimed to evaluate the correlation between the development of treatment-related peripheral neuropathy and the efficacy of nab-P/Gem combination in these patients. mPC patients treated with nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 as a first-line therapy were included. Treatment-related adverse events, mainly peripheral neuropathy, were categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02. Efficacy outcomes, including overall survival (OS), progression-free survival (PSF), and disease control rate (DCR), were estimated by the Kaplan–Meier model. A total of 153 patients were analyzed; of these, 47 patients (30.7%) developed grade 1–2 neuropathy. PFS was 7 months (95% CI (6–7 months)) for patients with grade 1–2 neuropathy and 6 months (95% CI (5–6 months)) for patients without peripheral neuropathy (p = 0.42). Median OS was 13 months (95% CI (10–18 months)) and 10 months (95% CI (8–13 months)) in patients with and without peripheral neuropathy, respectively (p = 0.04). DCR was achieved by 83% of patients with grade 1–2 neuropathy and by 58% of patients without neuropathy (p = 0.03). In the multivariate analysis, grade 1–2 neuropathy was independently associated with OS (HR 0.65; 95% CI, 0.45–0.98; p = 0.03). nab-P/Gem represents an optimal first-line treatment for mPC patients. Among possible treatment-related adverse events, peripheral neuropathy is the most frequent, with different grades and incidence. Our study suggests that patients experiencing CINP may have a more favorable outcome, with a higher disease control rate and prolonged median survival compared to those without neuropathy. [ABSTRACT FROM AUTHOR]

Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician's therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer. [ABSTRACT FROM AUTHOR]