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The curing process of polydimethylsiloxane (PDMS) coating was systematically investigated by nonisothermal differential scanning calorimeter (DSC), and accordingly, the thermodynamic as well as kinetic parameters were obtained. Meanwhile, effect of structural factors, including different divinyl-terminated polydimethylsiloxane (ViPDMSVi), divinyl-terminated polymethylvinylsiloxane (ViPMVSVi), polymethylhydrosiloxane (PMHS), and reinforcing filler content, on mechanical and thermal properties of coating was studied. The results demonstrated that platinum compounds could significantly accelerate the hydrosilylation and reduce the curing temperature and activation energy. The viscosity, vinyl/hydrogen sites, and quantities of ViPDMSVi, ViPMVSVi, and PMHS were important factors to influence mechanical and thermal properties. Low viscosity ViPDMSVi and PMHS with side hydrogen atoms could increase crosslinking density, and then enhance the tensile strength and heat resistance. ViPMVSVi with higher viscosity and vinyl content could dramatically improve tensile strength while maintaining breaking elongation. Reinforcing filler was another vital factor to enhance strength and thermostability. 550% improvement in tensile strength occurred when reinforcing filler content was 40 wt%. All aforementioned results provided a comprehensive guidance for the preparation and property regulation of PDMS coating. This kind of PDMS coating can be applied in synthetic leather manufacturing. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of platinum(II) complex bearing 3′-aminothiocyclohexanespiro-5′-hydantoin as ligand. The complex was characterized by IR, NMR spectral analyses, elemental analyses and density functional theory (DFT) calculations. Cytotoxicity and inhibitory potential on xanthine oxidase (XO) were evaluated by performed docking calculations. The cytotoxic activities of the 3′-aminothiocyclohexanespiro-5′-hydantoin (1), its Pt(II) complex (2), thiocyclohexanespiro-5′-hydantoin (3), and its platinum complex (4) were assessed against HL-60 and MDA-MB-231 cells in comparison with the antiproliferative activity of cisplatin as a referent. The ligands (1 and 3) did not exhibit in vitro antitumor efficacy on either of the human tumor cell lines. Complex 2 showed higher antitumor activity (IC50 = 42.1 ± 2.8 μM on HL-60 and 97.8 ± 7.5 μM against MDA-MB-231 cells) than complex 4 (IC50 = 89.6 ± 2.8 μM on HL-60 and 112.5 ± 4.2 μM in MDA-MB-231 cells). IC50 values of cisplatin as referent were 8.7 ± 2.4 μM on HL-60 and 31.6 ± 5.4 μM on MDA-MB-231 cell lines. The inhibitory activity of ligands and complexes against XO, evaluated in vitro, were compared with allopurinol (IC50 = 1.70 ± 0.51 μM) as standard inhibitor. The platinum(II) complexes (2 and 4) inhibited the activity of XO, with IC50 values 110.33 ± 26.38 μM and 115.45 ± 42.43 μM, respectively, while the ligands 1 and 3 did not show higher degrees of inhibition at concentrations lower than 150 μM. The inhibitory potential against XO might be a possible precedent resulting in improved profile and anticancer properties. [ABSTRACT FROM AUTHOR]

Simple Summary: In ovarian cancer (OC), platinum-based therapy remains the front-line therapy, but drug resistance is common. In the current study, we analyzed two Gene Expression Omnibus (GEO) datasets to identify the responsible genes involved in the mechanism of platinum resistance. Thirteen co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis. Mechanism research revealed that NR2F1 promotes epithelial-mesenchymal transition (EMT) through TGFβ-1 signaling, participating in platinum resistance. We also found that NR2F1 was positively correlated with the infiltration of immunosuppressive cancer-associated fibroblasts (CAFs). Higher expression of NR2F1 was correlated with a poorer response to immune check blockades including anti-PD-L1. In the future, by analyzing the expression status of NR2F1 and the effect of platinum and immunotherapy in the clinical setting, it is expected that NR2F1 will be established as an effective drug selection marker, guiding treatment selection in OC patients. The mechanism underlying platinum resistance in ovarian cancer (OC) remains unclear. We used bioinformatic analyses to screen differentially expressed genes responsible for platinum resistance and explore NR2F1′s correlation with prognostic implication and OC staging. Moreover, Gene-set enrichment analysis (GSEA) and Gene Ontology (GO) analyses were used for pathway analysis. Epithelial-mesenchymal transition (EMT) properties, invasion, and migration capacities were analyzed by biochemical methods. The association between NR2F1 and cancer-associated fibroblast (CAF) infiltration and immunotherapeutic responses were also researched. A total of 13 co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis and positively correlated with OC staging. GSEA and GO analysis suggested the induction of EMT via TGFβ-1 might be a possible mechanism that NR2F1 participates in resistance. In vitro experiments showed that NR2F1 knockdown did not affect cell proliferation, but suppressed cell invasion and migration with or without cisplatin treatment through the EMT pathway. We also found that NR2F1 could regulate TGF-β1 signaling, and treating with TGF-β1 could reverse these effects. Additionally, NR2F1 was predominantly associated with immunosuppressive CAF infiltration, which might cause a poor response to immune check blockades. In conclusion, NR2F1 regulates TGF-β1-mediated EMT affecting platinum sensitivity and immune response in OC patients. [ABSTRACT FROM AUTHOR]

Cisplatin was originally discovered through its antibacterial action and subsequently has found use as a potent broad‐spectrum anticancer agent. This study determines the effect of growth media and solvent on the antibacterial activity of cisplatin and its analogue, oxaliplatin. Escherichia coli MG1655 or MG1655 ΔtolC was treated with the platinum compounds under different conditions and susceptibility was determined. Our results showed that DMSO reduced the activity of cisplatin by fourfold (MIC 12·5 mg l−1) compared with 0·9% NaCl‐solubilized cisplatin (MIC 3·12 mg l−1) when tested in MOPS. Surprisingly, complete loss of activity was observed in Mueller–Hinton Broth II (MHB II). By supplementing MOPS with individual components of MHB II such as the sulphur‐containing amino acids, l‐cysteine and l‐methionine, individually or in combination reduced activity by ≥8‐fold (MIC ≥25 mg l−1). Oxaliplatin was less active against E. coli (MIC 100 mg l−1) but exhibited similar inactivation in the presence of DMSO, MHBII or MOPS spiked with l‐cysteine and l‐methionine (MIC ≥400 mg l−1). Our data suggest that the antibacterial activity of cisplatin and oxaliplatin is modulated by both choice of solvent and composition of growth media. We demonstrate that this is primarily due to sulphur‐containing amino acids cysteine and methionine, an essential component of the recommended media for testing antimicrobial susceptibility, MHBII. [ABSTRACT FROM AUTHOR]

Substitution reactions of [2-(pyridinecarboxamide)dichloride Pt(II)] [PtCl2], [N-phenyl-(2-pyridinecarboxamide)dichloride Pt(II)] [PhPtCl2], [N-(4-methylphenyl)-2-pyridinecarboxamide)dichloride Pt(II)] [CH3PhPtCl2], [N-(4-methoxyphenyl)-(2-pyridine-carboxamide)dichloride Pt(II)] [CH3OPhPtCl2] and [N-(4-fluorophenyl)-(2-pyridinecarboxamide)dichloride Pt(II)] [FPhPtCl2], with nucleophiles; thiourea (TU), N,N′-dimethylthiourea (DMTU) and N,N,N′,N′-tetramethylthiourea (TMTU) were studied under pseudo first-order conditions. The rates of substitution were investigated as a function of nucleophile concentration and temperature using stopped-flow and UV-visible absorption spectrophotometers. Substitutions of the two coordinated chloride ligands of the Pt(II) complexes occur consecutively, with the first substitution occurring opposite the coordinated pyridyl. The observed pseudo first-order rate constants regressed linearly with concentration of the incoming nucleophiles according to the equation kobs = k2[Nu]. The highest substitution rates were measured for PtCl2, which is attributed to the unsubstituted non-leaving carboxamide ligand. The Pt(II) center of this complex is the most electrophilic as a result of the strong withdrawal of electron density through π-resonance by the carboxamide group. The introduction of a 4′-substituted phenyl group on the amido N of the carboxamide reduces the reactivity of the complexes due to proportional electronic effects from the ancillary substituents on the phenyl ring as well as its conformational disposition with respect to the plane of the complex. The order of reactivity of studied nucleophiles is TU > DMTU > TMTU. The substitution is associatively activated as supported by the negative entropy of activation values for the reactions. [ABSTRACT FROM AUTHOR]

PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64–0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64–0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab. [Display omitted] • We report the main second progression-free survival analysis of PAOLA-1. • Median second progression-free survival was significantly longer with olaparib + bevacizumab (bev) versus bev alone. • Addition of maintenance olaparib to bev provided benefit beyond first progression. • No new safety signals for olaparib were identified with longer follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Irreversible bilateral sensorineural hearing loss is a common side effect of platinum compounds. Because of the extended overall survival, a prolonged hearing surveillance and management of hearing impairments are emerging concerns for pediatric oncology. Methods: In this retrospective observational study, we enrolled 38 children out of 116 treated at our institution by chemotherapy (cisplatin and/or carboplatin) with or without irradiation between 2007 and 2014, submitted to hearing monitoring before every cycle of chemotherapy, and who completed a 5-year long-term audiological follow-up. Chemotherapy regimens, demographic findings, cumulative doses, and cranial irradiation were compared. Results: At the end of 5-year follow-up, ototoxicity was significantly increased compared to that observed at the end of chemotherapy (52.5% vs 39.5%, p < 0.001). A late onset of hearing loss was experienced in 13.1% of children, while in 26.3% progressive hearing loss was measured. Deafness at the end of chemotherapy and irradiation were significant prognostic factors for late ototoxicity outcomes (Odds Ratio 7.2—CI 1.67–31.1—p < 0.01 and 5.25—CI 1.26–21.86—p < 0.01 respectively). No significant differences were found between cisplatin and combined treatment (i.e., cisplatin shifted to carboplatin during monitoring for the onset of ototoxicity) and ototoxicity was not associated with platinum compounds cumulative dose (p > 0.05). 13.1% of children needed hearing aids at the end of follow-up. Conclusion: Long-term monitoring of at least 5 years prevents the harmful effects of hearing deprivation identifying late onset/progressive hearing loss after platinum compound chemotherapy in children thanks to early hearing rehabilitation, especially in those who underwent multimodal therapy or subjected to irradiation. [ABSTRACT FROM AUTHOR]

Organometallic molecules offer some of the most promising scaffolds for interaction with G‐quadruplex nucleic acids. We report the efficient synthesis of a family of organoplatinum(II) complexes, featuring a 2‐([2,2′‐bipyridin]‐6‐yl)phenyl tridentate (N∧N∧C) ligand, that incorporates peripheral side‐chains aiming at enhancing and diversifying its interaction capabilities. These include a di‐isopropyl carbamoyl amide, a morpholine ethylenamide, two enantiomeric proline imides and an oxazole. The binding affinities of the Pt‐complexes were evaluated via UV‐vis and fluorescence titrations, against 5 topologically‐distinct DNA structures, including c‐myc G‐quadruplex, two telomeric (22AG) G‐quadruplexes, a duplex (ds26) and a single‐stranded (polyT) DNA. All compounds exhibited binding selectivity in favour of c‐myc, with association constants (Ka) in the range of 2–5×105 M−1, lower affinity for both folds of 22AG and for ds26 and negligible affinity for polyT. Remarkable emission enhancements (up to 200‐fold) upon addition of excess DNA were demonstrated by a subset of the compounds with c‐myc, providing a basis for optical selectivity, since optical response to all other tested DNAs was low. A c‐myc DNA‐melting experiment showed significant stabilizing abilities for all compounds, with the most potent binder, the morpholine‐Pt‐complex, exhibiting a ΔTm>30 °C, at 1 : 5 DNA‐to‐ligand molar ratio. The same study implied contributions of the diverse side‐chains to helix stabilization. To gain direct evidence of the nature of the interactions, mixtures of c‐myc with the four most promising compounds were studied via UV Resonance Raman (UVRR) spectroscopy, which revealed end‐stacking binding mode, combined with interactions of side‐chains with loop nucleobase residues. Docking simulations were conducted to provide insights into the binding modes for the same four Pt‐compounds, suggesting that the binding preference for two alternative orientations of the c‐myc G‐quadruplex thymine 'cap' ('open' vs. 'closed'), as well as the relative contributions to affinity from end‐stacking and H‐bonding, are highly dependent on the nature of the interacting Pt‐complex side‐chain. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for the treatment. R0 resection refers to a microscopically negative margin on resection, where no gross or microscopic tumour remains in the primary tumour. We aimed to find evidence on the relative effectiveness of neoadjuvant therapies for patients with advanced gastroesophageal and gastric cancer on the R0 resection rate. Methods: Relevant randomised controlled trials were searched using appropriate keywords in health-related databases. We performed network meta-analysis within a frequentist framework. The endpoint assessed was the R0 resection rate. We assessed consistency and transitivity assumptions that are necessary for network meta-analysis. This study only used data from published studies. The need for consent from participants was waived by the Ethics Review Committee of the International Medical University in Malaysia. Results: Six randomised controlled trials involving 1700 patients were identified. A network plot was formed with five neoadjuvant regimens [DLX (pyrimidine analogue + platinum compounds + chemoradiotherapy), DELX (pyrimidine analogue + epipodophylllotoxins/etoposide + platinum compounds + chemoradiotherapy), ADL (anthracycline + pyrimidine analogue + platinum compounds), ADM (anthracycline+ pyrimidine analogue + anti-folate compounds) and LTX (platinum compounds + taxane + chemoradiotherapy)] and surgery alone for management of patients with advanced gastroesophageal and gastric cancer. Assumptions required for a network meta-analysis such as consistency ((global test: Chi2 (1): 3.71; p:0.054)), and the transitivity in accord to the characteristics of interventions considered in this review were not violated. In the network comparison, surgery alone has a lower R0 resection rate compared with LTX (OR 0.2, 95%CI:0.01, 0.38) or DLX (OR 0.48, 95%CI: 0.29, 0.79). LTX has higher resection rate compared with DLX (OR 2.47, 95%CI: 1.08 to 5.63), DELX (OR 106.0, 95%CI: 25.29 to 444.21), ADM (OR 5.41, 95%CI: 1.56 to 18.78) or ADL (OR 3.12, 95%CI: 1.27 to 7.67). There were wide or very wide CIs in many of these comparisons. Overall certainty of the evidence was low or very low. Further research in this field is very likely to have an important impact on our confidence in the R0 resection rates between LTX versus other neoadjuvant chemotherapy is likely to change the estimate. Conclusions: Findings suggest that overall quality of evidence on the relative effectiveness of neoadjuvant chemotherapies was low to very low level. Therefore, we are very uncertain about the true effect of neoadjuvant therapies in the R0 resection rate in patients with gastroesophageal and gastric cancer. Future well-designed large trials are needed. To recruit large samples in this field, multicountry trials are recommended. Future trials also need to assess treatment-related adverse events, and patients-centered outcomes such as health‐related quality of life. [ABSTRACT FROM AUTHOR]

Background. Most patients with small-cell lung cancer (SCLC) have extensive-stage (ES) disease with a poor prognosis. Immunotherapy has shown good therapeutic effects in the treatment of ES-SCLC. We performed a real-world retrospective study to evaluate the safety and efficacy of PD-L1 inhibitors plus chemotherapy in patients with ES-SCLC. Method. A total of 224 patients diagnosed with ES-SCLC between March 2017 and April 2021 were included, of which 115 received only etoposide-platinum (EP) chemotherapy,and 109 received programmed cell-death ligand 1 (PD-L1) inhibitors and EP. Results. Immune checkpoint inhibitors (ICIs) plus platinum were associated with a significant improvement in overall survival (OS), with a hazard ratio (HR) of 0.60 (95% CI, 0.42–0.85; P = 0.0054); median OS was 19 months in the ICIs plus EP group vs. 12 months in the EP group. The median progression-free survival (PFS) was 8.5 and 5.0 months, respectively (HR for disease progression or death, 0.42; 95% CI, 0.31–0.57; P < 0.0001). Male patients <65 years old, Stage IV, PS 0-1, without liver and brain metastasis had a better OS in the ICIs plus EP group than the EP group. The PFS and OS in the durvalumab plus chemotherapy group were insignificantly longer than that of the atezolizumab plus chemotherapy group. Any adverse effects (AEs) of grade 3 or 4 occurred in 50 patients (45.9%) in the ICIs plus EP group and 48 patients (41.7%) in the EP alone group. The most common immune-related AEs (irAEs) were immune hypothyroidism events (17.1%, 7/41), immune dermatitis (9.8%, 4/41), and immune pneumonia (9.8%, 4/41) in the durvalumab plus platinum-etoposide group. Immune liver insufficiency (10.3%, 7/68) and immune hypothyroidism (8.8%, 6/68) were the most common irAEs in the atezolizumab plus platinum-etoposide group. Conclusion. This study shows that adding PD-L1 inhibitors to chemotherapy can significantly improve PFS and OS in patients with ES-SCLC and demonstrates its safety without additional AEs. [ABSTRACT FROM AUTHOR]

Platinum-based compounds are actively used in clinical trials as anticancer agents. In this study, two novel platinum complexes, (C1 = [PtCl2(N(SO2quin)dpa)], C2 = [PtCl2(N(SO2azobenz)dpa)]) containing quinoline and azobenzene appended dipicolylamine sulfonamide ligands were synthesized in good yield. The singlet attributable to methylene CH2 protons of the ligands of C1 and C2 appears as two doublets in 1H NMR spectra, which confirms the presence of magnetically nonequivalent protons upon coordination to platinum. Structural data of N(SO2quin)dpa (L1), N(SO2azobenz)dpa (L2) and PtCl2(N(SO2quin)dpa) confirmed the formation of the desired compounds. Time-dependent density functional theory calculations suggested that the excitation of L1 show quin-unit-based π⟶π ∗ excitations (i.e., ligand-centered charge transfer, LC), while C1 shows the metal-ligand-to-ligand charge-transfer (MLLCT) character. L1 displays intense fluorescence from the 1LC excited state, while C1 gives phosphorescence from the 3LC state. Mammalian cell toxicity of ligands and complexes was assessed with NCI–H292 nonsmall-cell lung cancer cells. Further, C1 and C2 showed significantly low IC50 values compared with N(SO2azobenz)dpa and PtCl2(N(SO2quin)dpa). Fluorescence imaging data of both ligands and complexes revealed the potential fluorescence activity of these compounds for biological imaging. All four compounds are promising novel candidates that can be further investigated on their usage as potential anticancer agents and cancer cell imaging agents. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, several agents have been tested in randomized clinical trials in addition to anthracycline and taxane-based neoadjuvant chemotherapy (NACT) in early-stage triple-negative breast cancer (TNBC) to improve pathological complete response rate and, ultimately, survival outcome. Platinum agents, immune checkpoint inhibitors (ICIs), and PARP-inhibitors are the most extensively studied, while established predictors of their efficacy are lacking. Based on the biological features of TNBC, the purpose of this review is to provide an overview of the role of platinum agents, immunotherapy, and novel target therapies in the neoadjuvant setting. Moreover, based on safety issues and financial costs, we provide an overview of potential biomarkers associated with increased likelihood of benefit from the addition of platinum, ICIs, and novel target therapies to NACT. Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptor and HER2 expression, and therefore a lack of therapeutic targets. Anthracyclines and taxane-based neoadjuvant chemotherapy have historically been the cornerstone of treatment of early TNBC. However, genomic and transcriptomic analyses have suggested that TNBCs include various subtypes, characterized by peculiar genomic drivers and potential therapeutic targets. Therefore, several efforts have been made to expand the therapeutic landscape of early TNBC, leading to the introduction of platinum and immunomodulatory agents into the neoadjuvant setting. This review provides a comprehensive overview of the currently available evidence regarding platinum agents and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, as well as the novel target therapies that are currently being evaluated in this setting. Taking into account the economic issues and the side effects of the expanding therapeutic options, we focus on the potential efficacy biomarkers of the emerging therapies, in order to select the best therapeutic strategy for each specific patient. [ABSTRACT FROM AUTHOR]

This review describes various platinum complexes including heterocyclic fragments such as gemcitabine, satraplatin, fuplatin, etc. and covers data published over the last 20 years concerning the effectiveness of using platinum-containing drugs in antitumor therapy. Preparations of various genesis, structure, and intracellular conformations and possible mechanisms of action, biochemical properties, and some physicochemical parameters of these compounds are considered. Adducts of different nature and geometric structure have different intracellular repair reactions, cleavage of functional groups, and interaction with untwisted DNA in affected cells. In turn, molecules capable of targeted drug delivery of substances such as fullerenes and their water-soluble derivatives fullerenols as well as polymeric compounds (in particular, cucurbituril) used in the synthesis of platinum-containing biologically active compounds are gaining increased interest. Thus, research is also being conducted on selective targeted delivery of platinum-containing series with reduced toxicity in parallel with the search for the most effective compounds. This review cites data on biological modeling of the effectiveness, mechanism, and kinetics of active platinum-containing drugs. An important aspect is that all antitumor substances are synthesized under rational accessible conditions and have logical pathways for continuing work on the synthesis of analogs capable of stimulating the apoptosis of cancer cells. [ABSTRACT FROM AUTHOR]

Objective: To observe the clinical efficacy and safety of pembrolizumab plus albumin-bound paclitaxel and nedaplatin as a first-line therapy in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: 35 patients with advanced ESCC and evaluable foci admitted in Changhai Hospital from March 2020 to September 2021 were included in this study. All patients were given pembrolizumab 200 mg and albumin-bound paclitaxel 130 mg/m² on day 1 and 8, and nedaplatin 70 mg/m² on day 1. The treatment was repeated every 21 days. Evaluation of tumor response was performed according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1). Adverse effects were graded using version 5.0 of the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Results: All 35 patients were available for evaluation, with 4 patients (11.4%) achieving complete response (CR), 21 patients (60.0%) partial response (PR), 10 patients (28.6%) stable disease (SD) and 0 patients progression disease (PD). The objective response rate (ORR) was 71.4%. The disease control rate (DCR) was 100%. The median progression free survival (PFS) was 13.4 months. The main adverse effects include bone marrow suppression, thyroid dysfunction, rash, fever, arthralgia, myalgia and alopecia. Treatment-related adverse events of grade 3 or higher occurred only in 3 patients (8.6%). Conclusion: Pembrolizumab plus albumin- bound paclitaxel and nedaplatin as a first-line treatment demonstrated feasible anti-tumor efficacy and manageable safety in patients with advanced ESCC. Randomized trials with expanded samples to evaluate this new combination strategy are warranted. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence supporting the use of taxane‐based chemotherapy combined with cetuximab to treat recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). This retrospective study aimed to explore treatment efficacy and safety in a first‐line setting. Methods: Fifty‐nine patients received ≤6 cycles of combined cetuximab, platinum compounds, and taxane (median follow‐up, 352 days). Kaplan–Meier survival curves were constructed. Results: The median patient age was 54 years (23–75 years; 50 males and 9 females). The most common distant metastatic site was the lung. Patients received ≥2 cycles chemotherapy (33 [55.9%] received cetuximab, paclitaxel, and carboplatin; 21 [35.5%] received cetuximab maintenance; median progression‐free survival, 7 months; overall survival, 12 months). The most common hematological toxicity was Grade 3 or 4 neutropenia, which was successfully managed through growth‐stimulating factors and dose modifications. No treatment‐associated deaths occurred. Conclusions: Combined cetuximab, platinum, and taxane is effective and tolerable in R/M HNSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Eligibility for secondary cytoreductive surgery (SCS) in ovarian cancer is dependent on multiple confounding factors. In this study, we evaluated the clinical characteristics of 262 patients with recurrent ovarian cancer to assess the impact of SCS on patient survival and establish simplified criteria for the selection of patients who would most likely be benefitted from SCS. We observed that the median survival was significantly longer in the patients who received SCS compared with those who received chemotherapy alone. As for the indication of the surgery, limited regional recurrence (single region or up to three regions with limited carcinomatosis) emerged as the simplified factor that could predict no residual disease after SCS. (1) Background: Multiple confounding factors influence the indications for secondary cytoreductive surgery (SCS) in patients with ovarian cancer (OC). We aimed to identify the factors associated with patients most likely to benefit from SCS. (2) Methods: We retrospectively reviewed the medical records of patients with recurrent ovarian cancer from 2003 to 2021. The potential factors influencing treatment outcomes and survival between patients who received chemotherapy alone and those who received SCS after recurrence were evaluated. (3) Results: Recurrent OC was identified in 262 patients, with a median age of 53 (20–80) years. Of these patients, 87.4% had an initial stage III/IV disease. Eighty-nine (34%) patients received SCS. The median survival was 41.0 (95% confidence interval [CI], 37.4–44.5) months and 88.0 (95% CI, 64.2–111.7) months in the chemotherapy and surgery groups, respectively. A multivariate analysis showed limited regional carcinomatosis (single region or up to three regions with limited carcinomatosis) (p = 0.045) as the only significant factor for predicting no residual disease after SCS. In platinum-sensitive recurrent patients with limited regional recurrence, the complete resection rate was 87.6%. (4) Conclusions: SCS had a significant impact on survival in the selected patient population. Limited regional recurrence (single region or up to three regions with limited carcinomatosis) may be a simple criterion for SCS in platinum-sensitive recurrent OC patients. [ABSTRACT FROM AUTHOR]

The non-linear voltage-dependent hysteresis (Hys(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (Vramp) through digital-to-analog conversion. Perturbations on this Hys(V) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys(V) in different types of ionic currents elicited by long-lasting triangular Vramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of Ih's Hys(V) activated by triangular Vramp, while dexmedetomidine, an agonist of α2-adrenoceptors, effectively suppressed Ih as well as diminished the Hys(V) strength of Ih. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the Ih's Hys(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased Ih's Hys(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of Ih's Hys(V) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys(V) strength of erg-mediated K+ current activated by triangular Vramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys(V) magnitude of M-type K+ current. Zingerone, a methoxyphenol, was found to attenuate Hys(V) (with low- and high-threshold loops) of L-type Ca2+ current induced by long-lasting triangular Vramp. The Hys(V) properties of persistent Na+ current (INa(P)) evoked by triangular Vramp were characterized by a figure-of-eight (i.e., ∞) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys(V) strength of INa(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys(V) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of INa(P). Taken together, the observed perturbations by these small-molecule modulators on Hys(V) strength in different types of ionic currents evoked during triangular Vramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo. [ABSTRACT FROM AUTHOR]

The synthesis of cis and trans geometrical isomers of platinum(II) complexes with a symmetric N-heterocyclic carbene ligand (MeNHC) is reported. These complexes were obtained from 1,3-dimethylimidazolium-2-carboxylate, a masked NHC precursor. Their cytotoxicity, oxidative nature, and antibacterial behavior were investigated. The highest cytotoxic effect (IC50 = 1.21 μM) was observed with the cis-[Pt(MeNHC)2Cl2] complex in the cervix cancerous cell line HeLa. [ABSTRACT FROM AUTHOR]

Metal-based chemotherapeutics, especially platinum complexes, are widely used in the treatment of various types of cancer. Recent studies have shown that palladium compounds have similar or even greater cytotoxic properties than platinum complexes. Juglone (5-hydroxy-1, 4 naphthoquinone), as a natural compound, has anti-tumor properties on various cancer cell lines. In this study, the complex of palladium (II) with juglon and phenanthroline was synthesized and its cytotoxicity property on MCF-7 (human breast cancer cell line) was evaluated. The fluorescence images have been presented to detect the anti-proliferative effect. The [Pd (Jug) (phen)]Cl complex was found to have more cytotoxic properties (IC50: 5.2 μM) on MCF-7 cell line than juglone (IC50: 12 μM). Furthermore, the interaction of the complex [Pd (Jug) (phen)]Cl with HSA, DNA, and 2JVU has been investigated using the molecular docking method. This compound is considered with the potential of anti-tumor activity and can be a good candidate for the next stages of in vitro and in vivo screening. [ABSTRACT FROM AUTHOR]

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown. Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay. 72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652). BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi. • The role of altered DNA damage repair pathways in BTC setting is already unknown. • We conducted a retrospective analysis on BTC patients treated with platinum salts. • BRCAness phenotype is an independent favourable prognostic factor for PFS. • BRCAness BTC patients seem to be more sensitive to platinum compounds. • Sequential strategies of platinum salts and PARP inhibitors should be tested. [ABSTRACT FROM AUTHOR]

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EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. Platinum doublets and chemoimmunotherapy showed similar response rates (20–25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3–6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20–25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival. • Platinum doublets and chemoimmunotherapy showed similar efficacy with ORR 20–25%. • TP53 mutations and brain metastases conferred shorter survival after platinum and TKI. • More tumour CD8+ and less Th1 cells were associated with longer overall survival. • No difference in outcome by exon20 insertion site or use of pemetrexed or bevacizumab. • Occasionally long responses under EGFR TKI for both 'near-' and 'far-loop' variants. [ABSTRACT FROM AUTHOR]

Maintenance treatment is standard of care for front-line (FL) and platinum-sensitive recurrent ovarian cancer (PSROC) following response to chemotherapy. Adverse events (AEs) on maintenance therapies are common and usually attributable to investigational treatments but could also be unrelated. Randomised controlled trial (RCT) with blinded placebo design is the gold standard for determining the relative differences in efficacy and AEs between treatment arms. We performed a meta-analysis to quantify AE rates in placebo arms of RCTs to determine AEs not due to investigational agents. We performed an electronic search to identify eligible RCTs in FL and PSROC settings. Data from placebo arms were extracted and pooled using the inverse variance method to determine the risk of any AE, overall and specific grade 3 or higher (G ≥ 3) AEs, and AE-related treatment delay, reduction and discontinuation. We identified 13 eligible RCTs (FL, N = 8; PSROC, N = 5) with 2224 patients who received placebo (FL, N = 1541; PSROC, N = 683). The majority experienced an AE of any grade (FL, 93.0%; PSROC, 95.2%). Substantial proportions experienced G ≥ 3 AEs (FL, 14.6%; PSROC, 18.2%). In the FL setting, AEs led to treatment delay in 14.4%, dose reduction in 4.1% and discontinuation in 2.6%. Findings were similar for PSROC: 8.4%, 5.5% and 2.1%, respectively. AEs not due to investigational agents are common in ovarian cancer patients in maintenance therapy RCTs. Potential explanations include the nocebo effect, residual toxicities from previous treatment or underlying disease. Further research is required to identify better approaches to assessing AEs in this population. • The majority of patients on maintenance placebo experienced adverse events (AEs). • AEs were associated with dose delays, reductions and discontinuation of placebo. • The underlying aetiology is complex and likely involves the nocebo phenomenon. • AEs in randomised trials may not reflect true investigational treatment toxicities. [ABSTRACT FROM AUTHOR]

Background: A previous trial showed that autologous ex‐vivo expanded NK cell (SNK01) treatment combined with pembrolizumab showed better efficacy than pembrolizumab monotherapy in advanced non‐small cell lung cancer (NSCLC). This study was a 2‐year follow‐up of that previous study to determine the long‐term efficacy of the combination treatment. Methods: This trial included 20 patients with advanced NSCLC with a PD‐L1 tumor proportion score of 1% or greater who failed prior to front‐line platinum‐based therapy. The patients received pembrolizumab with low‐dose SNK01 (2 × 109 cells/dose) or high‐dose SNK01 (4 × 109 cells/dose), or pembrolizumab monotherapy. The primary study endpoint was overall survival (OS), and the secondary endpoint was progression‐free survival (PFS). Results: Two patients were excluded following serious adverse events. Among the 11 patients who died, five were from the NK groups (41.6%, n = 5/12), and six received pembrolizumab monotherapy (100%, n = 6/6). The estimated 2‐year survival rate was 58.3% versus 16.7% (pembrolizumab plus SNK01 vs. pembrolizumab monotherapy). The hazard ratio of pembrolizumab plus SNK01 compared with pembrolizumab monotherapy was 0.32 (95% CI: 0.1, 1.08, p‐value: 0.066). Although the median PFS was significantly higher in the pembrolizumab plus SNK01 group than in the pembrolizumab alone group, OS and PFS did not differ statistically between patients who received low doses of NK cells and those who received high doses of NK cells. Conclusions: Autologous NK cells can enhance the long‐term OS and PFS for NSCLC. A larger study is needed to confirm this result. Clinical Research Information Service number: KCT0003463. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate the role of skin tests (ST) in the diagnosis of hypersensitivity reactions (HSRs) with platinum salts (PS) and taxane (TX) groups drugs and their reliability in patient management. Materials and Method: Patients' data who developed immediate HSR with PS and TX were recorded and ST was performed. The gradual challenge was applied to all patients with ST negative and grade 1–2 with the suspect drug. Results: In total, the data of 104 patients (74 with PS, 30 with TX) who developed HSR against PS and TX were shared. The gradual challenge was applied to 72 ST negative and grade 1–2 patients (46 PS group, 26 TX group). The gradual challenge was negative in 39 patients in the PS group and 23 patients in the Tx group. The negative predictive value (NPV) for PS was 83% and NPV for TX was 88%. We found significantly higher skin test positivity in patients with PS and TX and grade 3 HSR (p = 0.007, p = 0.001). A significant correlation was found between skin test positivity and early onset of symptoms (p = 0.001 for PS, p = 0.015 for TX). In terms of symptoms witnessed in HSR, we observed the itching, urticaria, hypotension, syncope, and abdominal pain symptoms significantly more in the group with a positive skin test (p < 0.024, p < 0.001, p < 0.001, p < 0.002, and p < 0.025, respectively). Conclusions: We found very high NPV values for PS and TX. We found that the gradual challenge applied to patients with negative skin tests is reliable if Grade 3 HSR is not observed and with this approach, unnecessary desensitization processes and/or drug alterations can be avoided. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the second most prevalent gynecological malignancy. Its prognosis is poor with a five-year survival rate of <50% with the available therapies. There is a constant need for new biological markers. Therefore, we conducted the present study to evaluate the association between human epidermal growth factor receptor (HER2) neu and the clinicopathological features of epithelial ovarian cancer. Method: A prospective, observational analytic study was conducted at Fauji Foundation Hospital, Rawalpindi between November 2018 and October 2019. It was a cross-sectional study with a quantitative correlational study design. Results: We recruited 90 patients. The mean age of diagnosis was 53 ± 8.022 years; 81.1% (n = 73) had raised pretreatment CA-125 levels with stage III (56.7%, n = 51) and grade III (54.4%, n = 49) at presentation. It was seen that 24.4% (n = 22) of the tumors expressed HER2/neu, 65.6% (n = 59) were negative and 10% (n = 9) were equivocal. 72.2% had platinum sensitive disease. According to HER2/neu status, 20% HER2/neu positive patients had platinum sensitive disease and 3.3% had resistant disease; meanwhile, 47.8% HER2/neu negative patients had platinum sensitive disease and 10% were platinum resistant. HER2/neu expression was significantly associated with grade (P = 0.040) and pretreatment CA-125 levels (P = 0.032) whereas our study failed to show a significant association between stage (P = 0.383) and chemotherapy response (P = 0.055). Conclusion: The current study demonstrated that HER2/neu was positive in 24.4% of the patients, which was significantly associated with grade and pretreatment CA-125 level. However, a longer follow-up is needed for survival analysis and establishment of HER2/neu as a prognostic marker for epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Metallodrug platinum compounds are indispensable components in the current standard combination for colorectal cancer treatment yet with severe additional adverse effects compromising the clinical outcomes. Having tumor microenvironment modulation and immunostimulatory effect, bio-compatible manganese (Mn) materials hold great promise for developing alternate metallodrug combination treatments. In this research, a novel MnO 2 -shelled nanoplatform was constructed to load two FDA-approved anti-tumor drugs, i.e., immunomodulatory curcumin (Cur) and immunostimulatory doxorubicin (Dox) to achieve enhanced dual-chemotherapy of primary tumors and remarkable inhibition of distant colorectal tumors. The experimental results have shown that MnO 2 efficiently enhanced Dox/Cur chemotherapy with significant primary tumor inhibition (81%) at very low dosages (5.0 and 1.0 mg/kg of Cur and Dox, respectively). Furthermore, the MnO 2 -assisted Dox/Cur chemotherapy promoted strong tumoricidal adaptive immune responses and overwhelmingly inhibited tumorigenesis in the tumor rechallenge experiment. This work has thus demonstrated the promising efficacy of the Mn/Dox/Cur nano-formulation and provided a novel way to improve immunostimulation of conventional chemotherapeutics using active metal oxide nanomaterials for colorectal cancer treatment. [ABSTRACT FROM AUTHOR]

New Pd(II) and Pt(II) complexes, [Pd(HL)Cl2] (C1) and [Pt(L)Cl] (C2) with ONN donor pincer ligand, 5-(diethylamino)-2-((Z)-((E)-(phenyl(pyridin-2-yl)methylene)hydrazono)methyl)phenol (HL) were synthesized and thoroughly characterized using spectroscopic techniques. X-ray structures of the complexes revealed that HL acts as bidentate N,N and tridentate O,N,N chelator in Pd(II) and Pt(II) complexes, respectively. The antiproliferative activity of the complexes was explored against four different human cancer (MCF-7, HCT116, A549, HepG2) cell lines. However, the maximum cytotoxicity was seen in the HepG2 cell line [IC50 = 6–12 μM] for both the complexes. IC50 for both complexes, C1 and C2, toward human peripheral blood mononuclear cells (hPBMC) cells were found to be >200 μM. The cytotoxicity of platinum complex (C2) was comparable to that of the cisplatin in HepG2 cell lines. [ABSTRACT FROM AUTHOR]

Simple Summary: Platinum-based agents are one of the most widely used chemotherapy drugs for various types of cancer. However, one of the main challenges in the application of platinum drugs is resistance, which is currently being widely investigated. Epigenetic DNA methylation-based biomarkers are promising to aid in the selection of patients, helping to foresee their platinum therapy response in advance. These biomarkers enable minimally invasive patient sample collection, short analysis, and good sensitivity. Hence, improved methodologies for the detection and quantification of DNA methylation biomarkers will facilitate their use in the choice of an optimal treatment strategy. Platinum-based chemotherapy is routinely used for the treatment of several cancers. Despite all the advances made in cancer research regarding this therapy and its mechanisms of action, tumor resistance remains a major concern, limiting its effectiveness. DNA methylation-based biomarkers may assist in the selection of patients that may benefit (or not) from this type of treatment and provide new targets to circumvent platinum chemoresistance, namely, through demethylating agents. We performed a systematic search of studies on biomarkers that might be predictive of platinum-based chemotherapy resistance, including in vitro and in vivo pre-clinical models and clinical studies using patient samples. DNA methylation biomarkers predictive of response to platinum remain mostly unexplored but seem promising in assisting clinicians in the generation of more personalized follow-up and treatment strategies. Improved methodologies for their detection and quantification, including non-invasively in liquid biopsies, are additional attractive features that can bring these biomarkers into clinical practice, fostering precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: With the introduction of immune checkpoint inhibitors (ICI) in recent years, the treatment landscape of metastatic urothelial cancer has undergone a substantial transformation. Nevertheless, disease progression after prior platinum-based chemotherapy and ICI pretreatment remains a challenging clinical situation with little evidence for following therapeutic options. The aim of this multicenter analysis was to examine the efficacy of the vinca alkaloid vinflunine after previous ICI therapy. In our cohort, post-ICI patients showed an overall response rate (ORR) of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and the clinical benefit rate (CBR) was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Our analysis demonstrates the clinical activity of vinflunine in a third- or later-line post-ICI setting, and the therapeutic benefit may be considerably higher than demonstrated in previous studies. Background: Immune checkpoint inhibitors (ICI) are standard of care in patients with metastatic urothelial carcinoma (mUC) ineligible for cisplatin, and as second-line therapy after platinum-based chemotherapy. To date, few data exist about the efficacy of the former second-line chemotherapeutic agent vinflunine after the failure of sequential platinum-based chemotherapy and ICI treatment. The aim of this analysis was to examine the efficacy of vinflunine in a post-ICI third- or later-line setting. Methods: In this retrospective German multicenter study, data of mUC patients treated with vinflunine were reviewed in six centers between February 2010 and December 2021. All of the 105 included patients had radiologic progression after first-line platinum-based chemotherapy. The objective was to describe the efficacy of vinflunine in terms of overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS) for post-ICI and ICI-naïve patients, respectively. Results: In our cohort, 61 patients (58.1%) had preceding immunotherapy before vinflunine administration, and 44 patients (41.9%) were ICI-naïve. Patients with ICI pretreatment showed an ORR of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and CBR was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Conclusion: This analysis supports the sequential use of vinflunine in post-ICI patients since the vinca-alkaloid retains a measurable clinical activity in these heavily pretreated patients. The therapeutic benefit may be higher than demonstrated in previous studies. [ABSTRACT FROM AUTHOR]

(1) Background: Since the discovery of cisplatin's cytotoxic properties, platinum(II) compounds have attracted much interest in the field of anticancer drug development. Over the last few years, classical structure–activity relationships (SAR) have been broken by some promising new compounds based on platinum or other metals. We focus on the synthesis and characterization of 17 different complexes with β-hydroxydithiocinnamic acid esters as O,S bidendate ligands for nickel(II), palladium(II), and platinum(II) complexes. (2) Methods: The bidendate compounds were synthesized and characterized using classical methods including NMR spectroscopy, MS spectrometry, elemental analysis, and X-ray crystallography, and their cytotoxic potential was assessed using in vitro cell culture assays. Data were compared with other recently reported platinum(II), ruthenium(II), and osmium(II) complexes based on the same main ligand system. (3) Results: SAR analyses regarding the metal ion (M), and the alkyl-chain position (P) and length (L), revealed the following order of the effect strength for in vitro activity: M > P > L. The highest activities have Pd complexes and ortho-substituted compounds. Specific palladium(II) complexes show lower IC50 values compared to cisplatin, are able to elude cisplatin resistance mechanisms, and show a higher cancer cell specificity. (4) Conclusion: A promising new palladium(II) candidate (Pd3) should be evaluated in further studies using in vivo model systems, and the identified SARs may help to target platinum-resistant tumors. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide, urging the need for new and more efficient therapeutic approaches. Ruthenium complexes have emerged as attractive alternatives to traditional platinum-based compounds in the treatment of CRC. This work aims to evaluate anti-CRC properties, as well as to identify the mechanisms of action of ruthenium complexes with the general formula [Ru(η5-C5H4R)(PPh3)(4,4′-R′-2,2′-bipyridine)][CF3SO3], where R = CH3, CHO or CH2OH and R′ = H, CH3, CH2OH, or dibiotin ester. The complexes (Ru 1–7) displayed high bioactivity, as shown by low IC50 concentrations against CRC cells, namely, RKO and SW480. Four of the most promising ruthenium complexes (Ru 2, 5–7) were phenotypically characterized and were shown to inhibit cell viability by decreasing cell proliferation, inducing cell cycle arrest, and increasing apoptosis. These findings were in accordance with the inhibition of MEK/ERK and PI3K/AKT signaling pathways. Ruthenium complexes also led to a decrease in cellular clonogenic ability and cell migration, which was associated with the disruption of F-actin cytoskeleton integrity. Here, we demonstrated that ruthenium complexes, especially Ru7, have a high anticancer effect against CRC cells and are promising drugs to be used as a new therapeutical strategy for CRC treatment. [ABSTRACT FROM AUTHOR]