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Introduction: Pemetrexed is a first line drug for brain metastases from lung cancer, either as monotherapy or combined with other drugs. The frequent occurrence of initial and acquired resistance to pemetrexed results in limited treatment effectiveness in brain metastases. CD146 was recently found to play important roles in chemoresistance and tumor progression. However, the underlying mechanisms of CD146's effects in pemetrexed resistance remain undefined. Method and results: Sensitivity to pemetrexed was assessed with a preclinical brain metastasis (BM) model based on lung adenocarcinoma PC9 cells. The role and mechanism of CD146 in pemetrexed resistance in non-small cell lung cancer (NSCLC) brain metastasis were explored in vitro and in vivo. A subpopulation of brain metastatic cells derived from progenitor PC9 cells (PC9-BrMS) was significantly resistant to pemetrexed. CD146 levels were significantly increased in pemetrexed resistant brain metastases, while CD146 inhibition suppressed pemetrexed resistance in BM cells. Mechanistically, CD146 mediated pemetrexed resistance in brain metastatic cells by promoting DNA damage repair, maintaining normal cell cycle progression, and regulating the NF-KB pathway to counter apoptosis, and these effects was based on increased DNA damage, cell cycle arrest, and occurrence of apoptosis after CD146 inhibition as well as the reemergence of pemetrexed resistance after CD146 restoration. Discussion: In summary, this study revealed that the resistance of NSCLC brain metastatic cells to PEM was dependent on CD146.Thus CD146 might be targeted in clinic to overcome pemetrexed resistance in brain metastases from NSCLC. [ABSTRACT FROM AUTHOR]

REV7, also known as MAD2B, MAD2L2, and FANCV, is a HORMA-domain family protein crucial to multiple genome stability pathways. REV7's canonical role is as a member of polymerase ζ, a specialized translesion synthesis polymerase essential for DNA damage tolerance. REV7 also ensures accurate cell cycle progression and prevents premature mitotic progression by sequestering an anaphase-promoting complex/cyclosome activator. Additionally, REV7 supports genome integrity by directing double-strand break repair pathway choice as part of the recently characterized mammalian shieldin complex. Given that genome instability is a hallmark of cancer, it is unsurprising that REV7, with its numerous genome maintenance roles, is implicated in multiple malignancies, including ovarian cancer, glioma, breast cancer, malignant melanoma, and small-cell lung cancer. Moreover, high REV7 expression is associated with poor prognoses and treatment resistance in these and other cancers. Promisingly, early studies indicate that REV7 suppression enhances sensitivity to chemotherapeutics, including cisplatin. This review aims to provide a comprehensive overview of REV7's myriad roles in genome maintenance and other functions as well as offer an updated summary of its connections to cancer and treatment resistance. [ABSTRACT FROM AUTHOR]

Most pancreatic cancer patients are diagnosed at advanced stages, with poor survival rates and drug resistance making pancreatic cancer one of the highest causes of cancer death in the UK. Understanding the underlying mechanism behind its carcinogenesis, metastasis and drug resistance has become an essential task for researchers. We have discovered that a well-established tumour suppressor, EPLIN, has an oncogenic rather than suppressive role in pancreatic cancer. Notably, upregulation of EPLIN was observed in pancreatic cancer samples compared to normal samples at RNA and protein levels. Moreover, the presence of EPLIN resulted in poor clinical outcomes in patients. We also report that inhibition of EPLIN led to reduced cellular growth and migration in pancreatic cancer cells. EPLIN regulates expression and phosphorylation levels of several key players in MAPK and PIK3CA-AKT signalling pathways, as well as key contributors of EMT. Furthermore, EPLIN mediates the inhibitory ability PIK3 kinases, MEK and ERK inhibitors have on cell migration. EPLIN was also found to have an impact on pancreatic cancer cells response to chemotherapeutic and EGFR/HER2 targeted therapeutic agents, namely gemcitabine, fluorouracil (5FU) and neratinib (Nerlynx). [ABSTRACT FROM AUTHOR]

This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX. [ABSTRACT FROM AUTHOR]

Chemotherapeutic resistance is one of the most common reasons for poor prognosis of patients with nasopharyngeal carcinoma (NPC). We found that CENPN can promote the growth, proliferation and apoptosis resistance of NPC cells, but its relationship with chemotherapeutic resistance in NPC is unclear. Here we verified that the CENPN expression level in NPC patients was positively correlated with the degree of paclitaxel (PTX) resistance and a poor prognosis through analysis of clinical cases. VAMP8 expression was significantly increased after knockdown of CENPN by transcriptome sequencing. We found in cell experiments that CENPN inhibited macroautophagy/autophagy and VAMP8 expression and significantly increased PTX resistance. Overexpression of CENPN reduced the inhibitory effects of PTX on survival, cell proliferation, cell cycle progression and apoptosis resistance in NPC cells by inhibiting autophagy. In turn, knockdown of CENPN can affect the phenotype of NPC cells by increasing autophagy to achieve PTX sensitization. Sequential knockdown of CENPN and VAMP8 reversed the PTX-sensitizing effect of CENPN knockdown alone. Experiments in nude mice confirmed that knockdown of CENPN can increase VAMP8 expression, enhance autophagy and increase the sensitivity of NPC cells to PTX. Mechanistic studies showed that CENPN inhibited the translocation of p-CREB into the nucleus of NPC cells, resulting in the decreased binding of p-CREB to the VAMP8 promoter, thereby inhibiting the transcription of VAMP8. These results demonstrate that CENPN may be a marker for predicting chemotherapeutic efficacy and a potential target for inducing chemosensitization to agents such as PTX. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; CENPN: centromere protein N; CQ: chloroquine; CREB: cAMP responsive element binding protein; ChIP: chromatin immunoprecipitation assay; IC50: half-maximal inhibitory concentration; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPC: nasopharyngeal carcinoma; NPG: nasopharyngitis; oeCENPN: overexpressed CENPN; PTX: paclitaxel; RAPA: rapamycin; RNA-seq: transcriptome sequencing; shCENPN: small hairpin RNA expression vector targeting the human CENPN gene; shCENPN-shVAMP8: sequential knockdown targeting the human CENPN gene and VAMP8 gene; shVAMP8: small hairpin RNA expression vector targeting the human VAMP8 gene; TEM: transmission electron microscopy; TIR: tumor inhibitory rate; VAMP8: vesicle associated membrane protein 8. [ABSTRACT FROM AUTHOR]

Background: Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown. Methods: PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches. Results: The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle. Conclusions: Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM. [ABSTRACT FROM AUTHOR]

Currently, traditional cancer treatment strategies are greatly challenged by the existence of cancer stem cells (CSCs), which are root cause of chemotherapy resistance. Differentiation therapy presents a novel therapeutic strategy for CSC‐targeted therapy. However, there are very few studies on the induction of CSCs differentiation so far. Silicon nanowire array (SiNWA) with many unique properties is considered to be an excellent material for various applications ranging from biotechnology to biomedical applications. In this study, we report the SiNWA differentiates MCF‐7‐derived breast CSCs (BCSCs) into non‐CSCs by modulating the morphology of cells. In vitro, the differentiated BCSCs lose the stemness properties and thus become sensitive to chemotherapeutic drugs, eventually leading to the death of BCSCs. Therefore, this work suggests a potential approach for overcoming chemotherapeutic resistance. [ABSTRACT FROM AUTHOR]

Aims: Among solid tumors, hypoxia is a common characteristic and responsible for chemotherapeutic resistance. Hypoxia-sensitive imaging probes are therefore essential for early tumor detection, growth monitoring and drug-response evaluation. Despite significant efforts, detecting hypoxic oxygen levels remains challenging. Materials & methods: This paper demonstrates the use of an amine-rich carbon dot probe functionalized with an imidazole group that exhibits reversible fluorescence switching in normoxic and hypoxic environments. Results & conclusion: We demonstrate the ability to emit near-infrared light only under hypoxic conditions. The probes are found to be biodegradable in the presence of human digestive enzymes such as lipase. Ex vivo tissue imaging experiments revealed promising near-infrared signals even at a depth of 5 mm for the probe under ex vivo imaging conditions. Hypoxia is the state where oxygen is not adequately available at the tissue level and is the common cause of resistance toward chemotherapeutics. Hence, probes that can detect hypoxia are important in detecting early tumor progression. Here in this paper, we have developed a fluorescent probe which helps in determining normoxic and hypoxic environments. This probe emits near-infrared light only under hypoxic conditions. The phenomena have been established herein by extensive experiments. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial‐mesenchymal transition (EMT), contributes to self‐renewal of cancer stem‐like cells (CSCs), chemo‐resistance, metastasis, and TNBC‐related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1‐mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven‐malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor‐promoting function and clinical significance of the CDK1‐USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo‐resistance and metastasis in TNBC. [ABSTRACT FROM AUTHOR]

Dysregulation of epigenetic mechanisms have been depicted in several pathological consequence such as cancer. Different modes of epigenetic regulation (DNA methylation (hypomethylation or hypermethylation of promotor), histone modifications, abnormal expression of microRNAs (miRNAs), long non-coding RNAs, and small nucleolar RNAs), are discovered. Particularly, lncRNAs are known to exert pivot roles in different types of cancer including breast cancer. LncRNAs with oncogenic and tumour suppressive potential are reported. Differentially expressed lncRNAs contribute a remarkable role in the development of primary and acquired resistance for radiotherapy, endocrine therapy, immunotherapy, and targeted therapy. A wide range of molecular subtype specific lncRNAs have been assessed in breast cancer research. A number of studies have also shown that lncRNAs may be clinically used as non-invasive diagnostic biomarkers for early detection of breast cancer. Such molecular biomarkers have also been found in cancer stem cells of breast tumours. The objectives of the present review are to summarize the important roles of oncogenic and tumour suppressive lncRNAs for the early diagnosis of breast cancer, metastatic potential, and chemotherapy resistance across the molecular subtypes. [ABSTRACT FROM AUTHOR]

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PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyomavirus small T (PolST) expression in mammalian cells. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at the midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through the cell cycle and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, and this underscores the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance. This article has an associated First Person interview with the first author of the paper. [ABSTRACT FROM AUTHOR]

Introduction: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. Methods: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. Results: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). Conclusion: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment. [ABSTRACT FROM AUTHOR]

We previously found that microRNAs play major roles in the maintenance of amoeboid‐like oral squamous cell carcinoma (OSCC) cells with high expression of CD44 (CD44high). However, the roles of microRNAs in chemotherapeutic resistance exhibited by CD44high amoeboid‐like OSCC cells are unclear. Here, docetaxel‐induced apoptosis was examined in CD44high OSCC cells (CD44high OM‐1 cells) cultured on laminin‐coated silicone gel. Amoeboid‐like CD44high OSCC cells exhibited robust resistance to docetaxel‐induced apoptosis and significant upregulation of miR‐224‐5p expression compared with epithelial‐like CD44high OSCC cells and mesenchymal‐like CD44high OSCC cells. The expression of pannexin‐1 (PANX1), a channel‐forming protein that regulates the release of ATP, was significantly upregulated following transfection of amoeboid‐like CD44high OSCC cells with an miR‐224‐5p inhibitor. These results suggest that miR‐224‐5p inhibits PANX1 expression. Furthermore, miR‐224‐5p inhibitor‐transfected amoeboid‐like CD44high OSCC cells exhibited significant enhancement of the proportion of apoptotic cells; however, this effect was significantly inhibited by knockdown of PANX1 with PANX1 small interfering RNA. Additionally, the miR‐224‐5p inhibitor‐enhanced extracellular ATP levels were significantly reduced by PANX1 knockdown. These findings imply that miR‐224‐5p plays a vital role in the resistance to docetaxel‐induced apoptosis by attenuating PANX1‐induced ATP discharge. Moreover, amoeboid‐like CD44high OSCC cells may be involved in chemotherapeutic resistance of OSCC. [ABSTRACT FROM AUTHOR]

Background: Platinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. Methods: Platinum drug‐sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain‐of‐function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. Results: The derivative brain metastatic subpopulations (PC9‐BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. Conclusions: Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM. [ABSTRACT FROM AUTHOR]

The incidence and mortality of colorectal cancer (CRC) have always been among the highest in the world, although the diagnosis and treatment are becoming more and more advanced. At present, the main reason is that patients have acquired drug resistance after long-term conventional drug treatment. An increasing number of evidences confirm the existence of cancer stem cells (CSCs), which are a group of special cells in cancer, only a small part of cancer cells. These special cell populations are not eliminated by chemotherapeutic drugs and result in tumor recurrence and metastasis after drug treatment. CSCs have the ability of self-renewal and multidirectional differentiation, which is associated with the occurrence and development of cancer. CSCs can be screened and identified by related surface markers. In this paper, the characteristic surface markers of CSCs in CRC and the related mechanism of drug resistance will be discussed in detail. A better understanding of the mechanism of CSCs resistance to chemotherapy may lead to better targeted therapy. [ABSTRACT FROM AUTHOR]

Background: The incidence rate of cervical cancer is the highest in the reproductive tract and is not sensitive to chemotherapy. An appropriate amount of anti-angiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called "vascular normalization." Endostar (a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent. Many reports about endostar involved the treatment of non-small cell lung cancer, fewer reports are on cervical cancer. Purpose: To determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer. Methods: In this study, the patients with cervical cancer within stage IIB2 were selected, endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy (NACT) before radical surgical operation was adopted, patients outcome and adverse reaction were followed up. The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging (DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software was used for statistical analysis of the study results. Results: Endostar enhanced the short-term (2 year) overall survival (OS), progression-free survival (PFS) rates for cervical cancer patients. All the same, endostar increased long-term (5 year) OS for cervical cancer patients. Endostar therapy exhibited with mild adverse reaction. MRI showed endostar+NACT further reduce tumor volume than NACT alone. The parameters of Ktrans, Ve for DEC-MRI in endostar group exhibited obviously increase than NACT group. Tumor vascular maturation index α-SMA/CD31 in endostar group increased obviously than NACT group, correspondingly Ki67 staining for tumor proliferative rates, lymphovascular space invasion in endostar group further declined than NACT group. The genes and proteins expression of VEGFR2, Notch1, Notch 4, Dll4, Jag1 were obviously downregulated in endostar group comparing to NACT group. Conclusion: Endostar restored vascular homeostasis in cervical cancer temporarily, enhanced chemotherapeutic agents effects in cervical cancer, increased patient OS ratio. Endostar+NACT treatment may provide a new target therapy for cervical cancer. [ABSTRACT FROM AUTHOR]

Platinum‐based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non‐cross‐resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)PtIV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross‐resistance, as an intrinsic property of the platinacycle, against multiplatinum‐resistant colorectal cancer (CRC) and castration‐resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs. [ABSTRACT FROM AUTHOR]

This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX. [ABSTRACT FROM AUTHOR]

Purpose: Bladder cancer (BC) ranks first in the incidence of urogenital tumors in China and second only to prostate cancer in the West. This study will clarify the roles and mechanism of lncRNA GHET1 in chemotherapeutic resistance of BC to Gemcitabine.Methods: The expression of GHET1 was examined using real-time quantitative PCR. Cell Counting Kit-8 assay was applied to analyze cell proliferation and Gemcitabine sensitivity. Cell apoptosis was detected using Annexin V-FITC/PI double-stained flow cytometry. The expression of ABCC1 protein was examined using Western blotting.Results: Firstly, the expression of GHET1 was up-regulated in BC, its high expression was relevant to high grade and muscle invasion of BC patients. Secondly, high expression of GHET1 was related to low Gemcitabine sensitivity of BC patients, and GHET1 was highly expressed in Gemcitabine-resistant BC cell lines. Thirdly, knockdown of GHET1 decreased the IC50 of Gemcitabine in Gemcitabine-resistant BC cell lines and advanced the Gemcitabine-induced cytotoxicity; GHET1 promoted Gemcitabine resistance in BC. Finally, knockdown of GHET1 also inhibited the expression of ABCC1 protein in Gemcitabine-resistant BC cells.Conclusions: High expression of GHET1 was related with the low sensitivity to Gemcitabine of BC; GHET1 contributed to chemotherapeutic resistance to Gemcitabine in BC through up-regulating ABCC1 expression. Our findings are helpful to expound the molecular mechanism of chemotherapeutic resistance in BC. [ABSTRACT FROM AUTHOR]

Lung cancer management remains a challenge due to its asymptomatic and late presentation when it is metastatic. The clinical response to the first-line platinum-based chemotherapy in patients with advanced lung cancer is disappointing due to the development of chemoresistance. Chemoresistance is a complex phenomenon. Mechanistic research using experimental models has yielded limited clinical results to help increase understanding for overcoming resistance. While the role of lung CSCs in conferring multidrug resistance has been postulated, experimental evidence remains associative and lacks in depth mechanistic inquisition. In the present study, using mouse and human lung adenocarcinoma cell lines and their respective paired CSC derivative cell lines that we generated, we identified cancer stem cell component of lung adenocarcinoma as the source that confers multidrug resistance phenotype. Mechanistically, Gstp1 confers cisplatin resistance in mouse and human lung CSC models, both in vitro and in vivo. Further, transcriptional activation of Gstp1 expression by MEK/ERK signaling underlies cisplatin resistance in lung CSC cells. Moreover, we show that GSTP1 expression is a poor diagnostic and prognostic marker for human lung adenocarcinoma, thus is of high clinical relevance. Taken together, we have provided mechanistic understanding of the lung CSC in mediating chemoresistance. [ABSTRACT FROM AUTHOR]

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma. Chemoresistance is an important problem in osteosarcoma. CCN2 promotes drug resistance in osteosarcoma. CCN2 increases ABCG2 protein expression and activation in osteosarcoma [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant chemotherapy (NAC) plays a pivotal role in the treatment of locally advanced breast cancer (LABC); however, breast cancer is a heterogeneous disease, individual responses to chemotherapy are highly variable. Therefore, the purpose of the current research is to identify biomarkers that can predict the chemotherapeutic response. Patients and methods: We recruited 78 patients with primary breast cancer who underwent taxane- and anthracycline-based NAC; these patients were divided into sensitive and resistant groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The microRNA microarray was conducted to explore differentially expressed miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) further validated the relationship between miR-4530 and chemosensitivity in breast cancer patients. Results: No significant differences were observed between the two groups regarding the clinicopathological characteristics. miR-4530 showed the most potential involving breast cancer chemosensitivity. Mechanically, RUNX2 was identified one of the direct targets of miR-4530 and responsible for breast cancer chemosensitivity. Conclusion: Our results revealed that elevated serum miR-4530 levels may sensitize breast cancer to taxane- and anthracycline-based NAC by suppressing RUNX2; therefore, this miRNA has the potential to be a new biomarker for predicting breast cancer chemosensitivity. [ABSTRACT FROM AUTHOR]

In order for a tumour to continue to grow and disseminate, it must acquire a new blood supply. Neovascularisation can be enacted by a number of different mechanisms. This dependence of tumour progression on an augmented vascular supply has been exploited by the development of anti‐angiogenic drugs, which are designed to inhibit new blood vessel formation or disrupt existing tumour‐associated vasculature, both leading to ischaemic–hypoxic tumour cell death. However, the clinical benefits of these therapeutic approaches are frequently variable and often transient, the neoplasm sometimes being able to use other neovascularisation mechanisms to maintain its blood supply and thus evade the current anti‐angiogenic therapy. Tumours may also develop a more malignant phenotype following this treatment. Clinical outcomes may be improved by simultaneously inhibiting different angiogenic pathways, abetted by more effective drug delivery regimens such as metronomic chemotherapy and the concurrent use of other antitumour modalities. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let‑7f‑5p expression was elevated in chemotherapy‑resistant CRC tissues compared with chemotherapy‑sensitive tissues. Furthermore, upregulating let‑7f‑5p increased the expression levels of the anti‑apoptotic proteins, B‑cell lymphoma 2 (Bcl‑2) and B‑cell lymphoma‑extra large (Bcl‑xL), and decreased the activity of caspase‑3 and caspase‑9 in CRC cells. By contrast, downregulating let‑7f‑5p yielded the opposite effect. Notably, the results indicated that let‑7f‑5p promoted chemotherapeutic resistance by directly repressing the expression of several pro‑apoptotic proteins, including tumor protein p53, tumor protein p53‑inducible nuclear protein 1, tumor protein p53‑inducible nuclear protein 2 and caspase‑3. Therefore, a novel mechanism by which let‑7f‑5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let‑7f‑5p may become an effective therapeutic strategy against CRC. [ABSTRACT FROM AUTHOR]

Interaction between the programmed cell death ligand 1 (PD‑L1) and programmed cell death 1 (PD‑1) contributes to tumor cell resistance to chemotherapeutic agents. PD‑L1 is expressed in the cells of diffuse large B‑cell lymphoma (DLBCL), one common type of malignant non‑Hodgkin lymphomas. However, little is known about how the PD‑1/PD‑L1 pathway functions in the pathogenesis of DLBCL. Therefore, the present study investigated whether and how the PD‑1/PD‑L1 axis is involved in regulating the sensitivity of CRL2631, a DLBCL cell line, to the CHOP (Cyclophosphamide, Hydroxydaunorubicin/adriamycin, Oncovin/vincristine and Prednisone) chemotherapeutic regimen. CHOP treatment significantly decreased cell survival rate and increased apoptosis in CRL2631 cells. The application of recombinant human PD‑1 (rPD‑1) significantly decreased the cytotoxic effects of the CHOP regimen in CRL2631 cells, but not in the CRL2631 cells with PD‑L1 deficiency. In the CRL2631 cells, rPD‑1 enhanced the activity of the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt1) pathway. However, the activity level of the PI3K/Akt1 pathway was decreased in CHOP‑treated CRL2631 cells. The selective PI3K inhibitor BKM120 significantly increased CHOP‑induced apoptosis, but this effect was abolished by rPD‑1 and aggravated by PD‑L1 knockdown. In CHOP‑treated PD‑L1 knockdown cells, the increased apoptosis was markedly inhibited by the overexpression of constitutively active Akt1. Overall, the results demonstrate that the over‑activated PD‑1/PD‑L1 axis is associated with chemotherapeutic resistance of DLBCL cells to the CHOP regimen, potentially through a PI3K‑dependent mechanism. [ABSTRACT FROM AUTHOR]

Abstract: The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies. [ABSTRACT FROM AUTHOR]

Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options. [ABSTRACT FROM AUTHOR]

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Background: Metastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression.Methods: Quantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3β pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3'untranslated region (3'UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR-200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry.Results: We found that miR-200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b-3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR-200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c-Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3β pathway.Conclusions: Our findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC. [ABSTRACT FROM AUTHOR]

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs. [ABSTRACT FROM AUTHOR]

Introduction and aim. 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic drug in the treatment of cholangiocarcinoma (CCA). Since development of drug resistance to 5-FU in CCA patients is the primary cause of treatment failure, a better understanding of the mechanism of drug resistance of this cancer is essential to improve the efficacy of 5-FU in CCA therapy. Material and methods. A 5-FU resistant CCA cell line (M214-5FUR) for a comparative chemo-resistance study was established. Real time RT-PCR was used to determine gene expression levels. Cell cytotoxicity was measured by the MTT assay. Protein expression levels were detected by the immunofluorescene method. Results. It was found that 5-FU resistance was associated with the overexpression of Tβ10 in CCA cell lines. 5-FU treatment at various concentrations induced the expressions of Tβ10 and ABC transporters (ABCB1, ABCG2 ABCA3) in two CCA cell lines, KKU-M055 and KKU-M214. M214-5FUR, a 5-FU-resistant cell line, exhibited a 5-FU resistant phenotype with a 16-fold extremely high expression of Tβ10 and ABC transporters, as compared to the parental cells, KKU-M214. siRNA targeted to Tβ10 significantly reduced expression of ABC transporters tested in the M214-5FUR cells (P < 0.05). Conclusions. The present novel findingsof Tβ10 connected with drug resistance as shown in this study provides a new insight for the therapeutic value of Tβ10 as a predictive biomarker of 5-FU chemoresistance. Inhibiting Tβ10 may be a valuable adjunct for suppression of ABC transporters and sensitizing chemotherapy treatment, especially 5-FU in CCA patients. [ABSTRACT FROM AUTHOR]

Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44CD24 cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44CD24 cells from spheres, we showed that CD44CD24 cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments . Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer. [ABSTRACT FROM AUTHOR]

At present, one of the major problems of cancer therapy is drug resistance. Breast cancer resistance protein (BCRP), a marker of the multidrug-resistant phenotype, affects drug absorption, distribution, metabolism, and excretion in normal tissues. Meanwhile, extracellular vesicles (EVs) have attracted increasing attention as a medium of cell-to-cell communication. However, the association between BCRP and circulating EVs remains unclear. The present study demonstrated that patients who did not respond or had progressive/ stable disease following chemotherapy had markedly higher BCRP levels compared to those that did not receive chemotherapy. Moreover, BCRP was upregulated at the mRNA and protein levels in tumor-derived circulating EVs from patients with a poor response to chemotherapy. Interestingly, the results also demonstrated that BCRP was co-expressed with MUC1, which is frequently expressed in breast cancer and is exported via EVs, and both BCRP and MUC1 were up-regulated after chemotherapy. In conclusion, the present study indicates that tumor-derived circulating EVs that carry BCRP may serve as a predictive biomarker of the response to chemotherapy for breast cancer. In addition, the results provide a window for individualized treatment to overcome resistance to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Introduction Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. Methods The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDAMB- 453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe TM DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. Results RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T- 47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional role of RasGRP3 in the altered behavior of these cells. Conclusions Taken together, our results suggest that the Ras activator RasGRP3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer. [ABSTRACT FROM AUTHOR]

The role of exosomes in cancer development has become the focus of much research, due to the many emerging roles possessed by exosomes. These micro-vesicles that are ubiquitously released in to the extracellular milieu, have been found to regulate immune system function, particularly in tumorigenesis, as well as conditioning future metastatic sites for the attachment and growth of tumor tissue. Through an interaction with a range of host tissue, exosomes are able to generate a pro-tumor environment that is essential for carcinogenesis. Herein, we discuss the contents of exosomes and their contribution to tumorigenesis, as well as their role in chemotherapeutic resistance and the development of novel cancer treatments and the identification of cancer biomarkers. [ABSTRACT FROM AUTHOR]

The treatment of anaplastic astrocytoma (AA) is controversial. New chemotherapeutic approaches are needed for AA treatment. Temozolomide (TMZ) is one of the chemotherapeutic drugs for the treatment of AA. The cytotoxic effects of TMZ can be removed by the MGMT (O(6)-methylguanine-DNA methyltransferase) enzyme. Then, chemotherapeutic resistance to TMZ occurs. MGMT inhibition by MGMT inactivators (such as lomeguatrib) is an important anticancer therapeutic approach to circumvent TMZ resistance. We aim to investigate the effect of TMZ-lomeguatrib combination on MGMT expression and TMZ sensitivity of SW1783 and GOS-3 AA cell lines. The sensitivity of SW1783 and GOS-3 cell lines to TMZ and to the combination of TMZ and lomeguatrib was determined by a cytotoxicity assay. MGMT methylation was detected by MS-PCR. MGMT and p53 expression were investigated by real-time PCR after drug treatment, and the proportion of apoptotic cells was analyzed by flow cytometry. When the combination of TMZ-lomeguatrib (50 μM) was used in AA cell lines, IC values were reduced compared to only using TMZ. MGMT expression was decreased, p53 expression was increased, and the proportion of apoptotic cells was induced in both cell lines. The lomeguatrib-TMZ combination did not have any effect on the cell cycle and caused apoptosis by increasing p53 expression and decreasing MGMT expression. Our study is a pilot study investigating a new therapeutic approach for AA treatment, but further research is needed. [ABSTRACT FROM AUTHOR]

Capecitabine is a chemotherapeutic drug used in patients with breast, colon and gastric cancer. Hand-foot syndrome (HFS) is a type of dermatitis that frequently occurs as a reaction to capecitabine. To date, no effective strategies have been found to prevent or reverse HFS. Furthermore, chemotherapy induces an elevation in the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), and this activation represents a critical mechanism for the induction of chemotherapeutic resistance. Adapalene is a third-generation synthetic retinoid. Topical retinoids are important therapeutic anti-aging agents for managing photo-damaged skin, and are known to increase HB-EGF levels, which is important for skin wound healing. Accordingly, the current report focused on the topical retinoids that increase HB-EGF expression in the skin, and we hypothesized that these topical retinoids induce local chemotherapeutic resistance in the skin of patients receiving chemotherapy and consequently, decrease the cutaneous side-effects of chemotherapy. This report presents a case of the successful treatment of refractory HFS induced by capecitabine using the topical application of adapalene. Topical adapalene was applied for 3 months and significantly reduced inflammation and pain following chemotherapy. Topical retinoids may have the potential to effectively treat capecitabine-induced HFS by increasing HB-EGF expression and decreasing cutaneous side-effects. Further studies are required to establish the therapeutic efficacy of topical retinoids on HFS. [ABSTRACT FROM AUTHOR]

Purpose: Hypoxia has been found to play an important role in regulating the biological characteristics of cancer stem cells (cCSCs). In this study, we tested whether a tumor hypoxic niche serves to the chemotherapeutic resistance of colon cCSCs. Methods: Each of 23 fresh samples of human colon adenocarcinoma was transplanted into nude mice. The tumor-bearing mice randomly and equally received (A) saline, (B) 5-fluorouracil (15 mg/kg), (C) oxaliplatin (10 mg/kg), and (D) oxaliplatin plus 5-fluorouracil when xenografts reached 250 mm ( n = 10). After 2-week treatment, tumor cells were quantified by flow cytometry for expression of CD133 and the hypoxic proportion of CD133 and CD133 cells which were also sorted and detected for ki67 and pimonidazole via immunofluorescence. Results: The hypoxic subpopulation of CD133 and CD133 cells was 66.5 and 26.4 %, respectively. Although there was no marked change for the hypoxic subpopulation of CD133 cells after treatment, the hypoxic fraction of proliferative CD133 cells was increased by 14.62, 16.45, and 20.46 % in groups B, C, and D, respectively. Furthermore, proliferative cells in CD133 and CD133 cells were reduced by 29.93 and 62.5 % in group C, and by 25.26 and 68.22 % in group D; in group B, however, the proliferative CD133 cells were increased by 37.09 %; the CD133 cells were unchanged. Conclusions: Most CD133 cCSCs are located in a hypoxic niche, where cCSCs are better at retaining proliferating property under chemotherapy. Oxaliplatin, rather than 5-FU, inhibits proliferation of cCSCs, which may be the mechanism underlying a better outcome by oxaliplatin in colon cancer patients. [ABSTRACT FROM AUTHOR]

Background: Synovial sarcoma, X breakpoint 2 interacting protein (SSX2IP), which has been identified as an acute myeloid leukemia associated antigen, is a potential target for leukemia immunotherapy. In rodents, its homologous gene, ADIP, plays an important role in the regulation of cell adhesion and migration, underlying its potential role in promoting metastasis of other cancers. Methods: To investigate the correlation between the expression level of SSX2IP and the clinicopathologic factors of hepatocellular carcinoma (HCC), 53 cases were studied by qPCR and statisted. To directly testing SSX2IP's contribution to HCC in animal models, 45 nude mice were enrolled in peritoneal spreading and liver metastasis models. For the migration and invasion assays, cell culture experiments were performed using QCMTM 24-Well Colorimetric Migration Assay Kit and Cell Invasion Assay Kit (Millipore). Moreover we examined the influence of SSX2IP overexpression on the chemosensitivity of hepatocellular carcinoma cells to two most common chemotherapy drugs (5-Fu and CDDP) using Cell counting kit-8 (CCK-8). The chemotherapeutic drugs sensitivity was evaluated by IC50 parameter. Results: Statistical analysis of clinical cases revealed that the SSX2IP high expression group had inclinations towards larger tumor size, more tumor thrombus and shorter survival period, implying a strong correlation between the expression level of SSX2IP and HCC tumorigenesis. Consistently in abdominal cavity metastasis and liver metastasis models of immune-deficient mice, SSX2IP was able to promote the metastasis of hepatoma cells. At the cytological level, SSX2IP stimulates the wound healing, metastasis and invasion of hepatoma cells, and reduces the sensitivity of hepatoma cells to 5-Fu and CDDP. Conclusions: Our results showed that SSX2IP promotes the development and metastasis of hepatocellular carcinoma and contributes to the drug resistance of hepatoma cells, suggesting that SSX2IP is expected to become a new diagnostic and prognostic marker and a new target of the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Concentration response experiments are utilized widely to characterize the response of tumor cell lines to chemotherapeutic drugs, but the assay methods are non-standardized and their analysis based on phenomenological equations. To provide a framework for better interpretation of these experiments, we have developed a mathematical model in which progression through the tumor cell cycle is inhibited by drug treatment via either cell cycle arrest or entrance into cell death pathways. By fitting concentration response data, preferably over a dynamic range, the contributions of these mechanisms can be delineated. The model was shown to fit well experimental data for three glioma cell lines treated with either carmustine or etoposide. In each cell line, the major mechanism of tumor cell inhibition was cell death for carmustine in contrast to cell cycle arrest for etoposide. The model also provides a possible interpretation for the acquired in vitro resistance of U87 cells to carmustine as an accelerated desensitization to cell killing effects. This approach will aid in understanding better the action of chemotherapeutic agents on tumor cells. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic ductal and lung adenocarcinomas are the most common and prevalent types of human neoplasms with a greater than 80% mortality rate. The poor prognosis of both these cancers are likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. Most notably, the early development of pancreatic intraepithelial neoplasia and lung lesions is suggested to be the result of a mutation in the K-ras (G12D) oncogene. Tumor necrosis factor-related-apoptosis-inducing-ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells, while leaving normal cells unharmed. However, some cancers show resistance to TRAIL treatment, leaving a gap in the understanding of its exact etiology. Methods: TRAIL-induced resistance to cell death was investigated in pancreatic and lung cancer cell lines. Cell survival was determined by SRB and apoptosis by ELISA-based cell death assay. Activation of bid and caspases were evaluated by Western blotting. Results: Our study demonstrated that TRAIL significantly suppressed cell survival, by inducing apoptosis in a dose-dependent manner, in the pancreatic cancer BxPC-3 (wild type G12) and lung cancer A549 (G12S) cell lines. In contrast, Panc-1 pancreatic and SK-LU-1 lung cancer cell lines, which have a mutated (G12D) K-ras genotype, were resistant to the actions of TRAIL. Conclusions: This study demonstrates an association between TRAIL resistance to apoptosis in human pancreatic and lung cancer cell lines and G12D K-ras mutation. [ABSTRACT FROM AUTHOR]

We describe a young man who presented with neurological signs and symptoms, and with a paraspinal soft tissue mass involving the vertebral body at T4. The patient was treated with dexamethasone prior to neurosurgical decompression and debulking. Biopsy showed features of a small B-cell lymphoma possibly of follicle center cell origin. The patient achieved complete remission with radiotherapy. However, he experienced relapse 10 months later with a soft tissue mass close to and involving the posteroinferior aspect of the sternum. Biopsy of the recurrent lesion showed features of B lymphoblastic leukemia/lymphoma. The first biopsy was revisited to demonstrate the lymphoblastic immunophenotype of the lesional cells. The 'indolent' appearance of the cells in the first biopsy was attributable to treatment with dexamethasone prior to the biopsy. [ABSTRACT FROM AUTHOR]

STAT proteins are cytoplasmic transcription factors that are involved in the regulation of numerous cellular activities such as cell growth, differentiation, and survival. In this study, we aimed to identify the expression pattern of STAT genes in imatinib-sensitive and -resistant K562 cells, and further, to reveal the effects of STAT5A siRNA knockdown on cell growth and apoptosis induction. The XTT cell proliferation assay showed that both sensitive and resistant K562 cells were sensitized to imatinib upon transfection with STAT5A siRNA. Caspase-3 enzyme activity was increased significantly in both cells. These results may open up new opportunities to overcome chemotherapeutic resistance in leukemia. [ABSTRACT FROM AUTHOR]

Development of novel therapy strategies is one of the major pressing topics of clinical oncology to overcome drug resistance of tumors. Artesunate (ART) is an antimalarial drug, which also exerts profound cytotoxic activity towards cancer cells. We applied a gene-hunting approach using microarray-based transcriptome-wide mRNA expression profiling and COMPARE analyses. We identified a set of genes, whose expression was associated either with high IC50 values or low IC50 values for ART. Therefore, these genes may function as resistance or sensitivity factors for response of tumor cells towards ART. This viewpoint is conceivable for genes involved in ribosomal activity, drug transport, cellular antioxidant defense, apoptosis, cell proliferation, cell cycle progression etc. An investigation of underlying signal transduction by pathway analysis suggested a role of the signaling pathways related to tumor necrosis factor (TNF) and the tumor suppressor p53. On the other hand, there were genes without obvious functional link to cellular response to ART, such as genes involved in the survival of cochlear outer and inner hair cells etc. We proved the hypothesis that ART influences the activity of transcription factors regulating downstream genes involved or not involved in response of cancer cells towards ART. This would explain the identification of genes with and without obvious relation to the cytotoxic activity of ART by microarray and COMPARE analyses. By analysis of the binding motifs for the transcription factors c-Myc and Max, we indeed found that 53 of 56 genes contained one or more binding sites for c-Myc/Max upstream of the gene-location. We conclude that c-Myc and Max-mediated transcriptional control of gene expression might contribute to the therapeutic effects of ART in cancer cells, but may also confer unwanted side effects by affecting therapy-unrelated genes. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways. [ABSTRACT FROM AUTHOR]