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Emerging strategies for sensitization of therapy resistant tumors toward cancer therapeutics by targeting the Bcl-2 family, TGF-β, Wnt/β-Catenin, RASSF and miRNA regulated signaling pathways

Veerasamy T, Eugin Simon S, Tan KO

Int J Biochem Cell Biol, 2021 08;137:106016.
PMID: 34082133 DOI: 10.1016/j.biocel.2021.106016

Conventional chemotherapy relies on the cytotoxicity of chemo-drugs to inflict destructive effects on tumor cells. However, as most tumor cells develop resistance to chemo-drugs, small doses of chemo-drugs are unlikely to provide significant clinical benefits in cancer treatment while high doses of chemo-drugs have been shown to impact normal human cells negatively due to the non-specific nature and cytotoxicity associated with chemo-drugs. To overcome this challenge, sensitizations of tumor cells with bioactive molecules that specifically target the pro-survival and pro-apoptosis signaling pathways of the tumor cells are likely to increase the therapeutic impacts and improve the clinical outcomes by reducing the dependency and adverse effects associated with using high doses of chemo-drugs in cancer treatment. This review focuses on emerging strategies to enhance the sensitization of tumor cells toward cancer therapies based on our understanding of tumor cell biology and underlying signaling pathways.

Matched MeSH terms: Drug Resistance, Neoplasm*
Fulltext Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer

Abdullah NA, Inman M, Moody CJ, Storr SJ, Martin SG

Invest New Drugs, 2021 10;39(5):1232-1241.
PMID: 33768386 DOI: 10.1007/s10637-021-01106-5

Radiotherapy is an effective treatment modality for breast cancer but, unfortunately, not all patients respond fully with a significant number experiencing local recurrences. Overexpression of thioredoxin and thioredoxin reductase has been reported to cause multidrug and radiation resistance - their inhibition may therefore improve therapeutic efficacy. Novel indolequinone compounds have been shown, in pancreatic cancer models, to inhibit thioredoxin reductase activity and exhibit potent anticancer activity. The present study evaluates, using in vitro breast cancer models, the efficacy of a novel indolequinone compound (IQ9) as a single agent and in combination with ionising radiation using a variety of endpoint assays including cell proliferation, clonogenic survival, enzyme activity, and western blotting. Three triple-negative breast cancer (MDA-MB-231, MDA-MB-468, and MDA-MB-436) and two luminal (MCF-7 and T47D) breast cancer cell lines were used. Results show that treatment with IQ9 significantly inhibited thioredoxin reductase activity, and inhibited cell growth and colony formation of breast cancer cells with IC50 values in the low micromolar ranges. Enhanced radiosensitivity of triple-negative breast cancer cells was observed, with sensitiser enhancement ratios of 1.20-1.43, but with no evident radiosensitisation of luminal breast cancer cell lines. IQ9 upregulated protein expression of thioredoxin reductase in luminal but not in triple-negative breast cancer cells which may explain the observed differential radiosensitisation. This study provides important evidence of the roles of the thioredoxin system as an exploitable radiobiological target in breast cancer cells and highlights the potential therapeutic value of indolequinones as radiosensitisers.***This study was not part of a clinical trial. Clinical trial registration number: N/A.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Generation of osimertinib-resistant cells from epidermal growth factor receptor L858R/T790M mutant non-small cell lung carcinoma cell line

Verusingam ND, Chen YC, Lin HF, Liu CY, Lee MC, Lu KH, et al.

J Chin Med Assoc, 2021 03 01;84(3):248-254.
PMID: 33009209 DOI: 10.1097/JCMA.0000000000000438

BACKGROUND: Lung cancer contributes to high cancer mortality worldwide with 80% of total cases diagnosed as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain serves as a druggable target in NSCLC patients with exon 19 deletion and L858R mutation. However, patients eventually succumbed to resistance to first- and second-generation EGFR-TK inhibitors through activation of T790M mutation. Third-generation EGFR-TKI, Osimertinib exhibits high efficacy in patients with exon 19 deletion/L858R/T790M mutation but they experienced acquired resistance thereafter. Available treatment options in NSCLC patients remains a challenge due to unknown molecular heterogeneity responsible for acquired resistance to EGFR-TKI. In this study, we aim to generate Osimertinib-resistant (OR) cells from H1975 carrying L858R/T790M double mutation which can be used as a model to elucidate mechanism of resistance.
METHODS: OR cells were established via stepwise-dose escalation and limiting single-cell dilution method. We then evaluated Osimertinib resistance potential via cell viability assay. Proteins expression related to EGFR-signalling, epithelial to mesenchymal transition (EMT), and autophagy were analyzed via western blot.
RESULTS: OR cell lines exhibited increased drug resistance potential compared to H1975. Distinguishable mesenchymal-like features were observed in OR cells. Protein expression analysis revealed EGFR-independent signaling involved in the derived OR cells as well as EMT and autophagy activity.
CONCLUSION: We generated OR cell lines in-vitro as evidenced by increased drug resistance potential, increased mesenchymal features, and enhanced autophagy activity. Development of Osimertinib resistance cells may serve as in-vitro model facilitating discovery of molecular aberration present during acquired mechanism of resistance.

Matched MeSH terms: Drug Resistance, Neoplasm*
LOC285629 regulates cell proliferation and motility in colorectal cancer cells

Nasir SN, Abu N, Ab Mutalib NS, Ishak M, Sagap I, Mazlan L, et al.

Clin Transl Oncol, 2018 Jun;20(6):775-784.
PMID: 29098557 DOI: 10.1007/s12094-017-1788-x

PURPOSE: Colorectal cancer (CRC) is one of the most widely diagnosed cancers in men and women worldwide. With the advancement of next-generation sequencing technologies, many studies have highlighted the involvement of long non-coding RNAs (lncRNAs) in cancer development. Growing evidence demonstrates that lncRNAs play crucial roles in regulating gene and protein expression and are involved in various cancers, including CRC. The field of lncRNAs is still relatively new and a lot of novel lncRNAs have been discovered, but their functional roles are yet to be elucidated. This study aims to characterize the expression and functional roles of a novel lncRNA in CRC.
METHOD: Several methods were employed to assess the function of LOC285629 such as gene silencing, qPCR, proliferation assay, BrdU assay, transwell migration assay, ELISA and protein profiler.
RESULTS: Via in silico analyses, we identified significant downregulation of LOC285629, a novel lncRNA, across CRC stages. LOC285629 expression was significantly downregulated in advanced stages (Stage III and IV) compared to Stage I (Kruskal-Wallis Test; p = 0.0093). Further in-house validation showed that the expression of LOC285629 was upregulated in colorectal cancer tissues and cell lines compared to the normal counterparts, but was downregulated in advanced stages. By targeting LOC285629, the viability, proliferative abilities, invasiveness and resistance of colorectal cancer cells towards 5-fluorouracil were reduced. It was also discovered that LOC285629 may regulate cancer progression by targeting several different proteins, namely survivin, BCL-xL, progranulin, PDGF-AA, enolase 2 and p70S6 K.
CONCLUSION: Our findings suggest that LOC285629 may be further developed as a potential therapeutic target for CRC treatment.

Matched MeSH terms: Drug Resistance, Neoplasm/genetics*
Fulltext Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer

Hon KW, Ab-Mutalib NS, Abdullah NMA, Jamal R, Abu N

Sci Rep, 2019 Nov 11;9(1):16497.
PMID: 31712601 DOI: 10.1038/s41598-019-53063-y

Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker. Exosomes are microvesicles released by body cells for intercellular communication. Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loops and enriched in exosomes. Crosstalk between circRNAs in exosomes and chemo-resistance in CRC remains unknown. This research aims to identify exosomal circRNAs associated with FOLFOX-resistance in CRC. FOLFOX-resistant HCT116 CRC cells (HCT116-R) were generated from parental HCT116 cells (HCT116-P) using periodic drug induction. Exosomes were characterized using transmission electron microscopy (TEM), Zetasizer and Western blot. Our exosomes were translucent cup-shaped structures under TEM with differential expression of TSG101, CD9, and CD63. We performed circRNAs microarray using exosomal RNAs from HCT116-R and HCT116-P cells. We validated our microarray data using serum samples. We performed drug sensitivity assay and cell cycle analysis to characterize selected circRNA after siRNA-knockdown. Using fold change >2 and p

Matched MeSH terms: Drug Resistance, Neoplasm*
Targeted polymeric nanoparticle for anthracycline delivery in hypoxia-induced drug resistance in metastatic breast cancer cells

Almoustafa HA, Alshawsh MA, Chik Z

Anticancer Drugs, 2021 Aug 01;32(7):745-754.
PMID: 33675612 DOI: 10.1097/CAD.0000000000001065

Poly lactic-co-glycolic acid (PLGA) nanoparticles are intensively studied nanocarriers in drug delivery because of their biodegradability and biochemical characteristics. Polyethylene glycol (PEG) coating for nanocarriers gives them long circulation time in blood and makes them invisible to the reticuloendothelial system. Breast cancer cells have greater uptake of hyaluronic acid compared to normal cells as it binds to their overexpressed CD44 receptors. Since hypoxia plays an important role in cancer metastasis; we formulated PEG-PLGA nanoparticles coated with hyaluronic acid as targeted delivery system for doxorubicin (DOX) using nanoprecipitation method, and characterized them for chemical composition, size, surface charge, shape, and encapsulation efficiency. Then we tested them in vitro on hypoxia-optimized metastatic breast cancer cells. The nanoparticles were spherical with an average size of about 106 ± 53 nm, a negative surface charge (-15 ± 3 mV), and high encapsulation efficiency (73.3 ± 4.1%). In vitro investigation with hypoxia-elevated CD44 MDA-MB-231 cells showed that hyaluronic acid-targeted nanoparticles maintained their efficacy despite hypoxia-induced drug resistance unlike free DOX and nontargeted nanoparticles. In conclusion, this study revealed a simple third generation nanoparticle formulation for targeted treatment of hypoxia-induced drug resistance in breast cancer metastatic cells. Further, optimization is needed including In vivo efficacy and nanoparticle-specific pharmacokinetic studies.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Fulltext Down-Regulation of MicroRNA-210 Confers Sensitivity towards 1'S-1'-Acetoxychavicol Acetate (ACA) in Cervical Cancer Cells by Targeting SMAD4

Phuah NH, Azmi MN, Awang K, Nagoor NH

Mol Cells, 2017 Apr;40(4):291-298.
PMID: 28401751 DOI: 10.14348/molcells.2017.2285

MicroRNAs (miRNAs) are short non-coding RNAs that regulate genes posttranscriptionally. Past studies have reported that miR-210 is up-regulated in many cancers including cervical cancer, and plays a pleiotropic role in carcinogenesis. However, its role in regulating response towards anti-cancer agents has not been fully elucidated. We have previously reported that the natural compound 1'S-1'-acetoxychavicol acetate (ACA) is able to induce cytotoxicity in various cancer cells including cervical cancer cells. Hence, this study aims to investigate the mechanistic role of miR-210 in regulating response towards ACA in cervical cancer cells. In the present study, we found that ACA down-regulated miR-210 expression in cervical cancer cells, and suppression of miR-210 expression enhanced sensitivity towards ACA by inhibiting cell proliferation and promoting apoptosis. Western blot analysis showed increased expression of mothers against decapentaplegic homolog 4 (SMAD4), which was predicted as a target of miR-210 by target prediction programs, following treatment with ACA. Luciferase reporter assay confirmed that miR-210 binds to sequences in 3'UTR of SMAD4. Furthermore, decreased in SMAD4 protein expression was observed when miR-210 was overexpressed. Conversely, SMAD4 protein expression increased when miR-210 expression was suppressed. Lastly, we demonstrated that overexpression of SMAD4 augmented the anti-proliferative and apoptosis-inducing effects of ACA. Taken together, our results demonstrated that down-regulation of miR-210 conferred sensitivity towards ACA in cervical cancer cells by targeting SMAD4. These findings suggest that combination of miRNAs and natural compounds could provide new strategies in treating cervical cancer.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Anti-proliferative and pro-apoptotic effects from sequenced combinations of andrographolide and cisplatin on ovarian cancer cell lines

Yunos NM, Mutalip SS, Jauri MH, Yu JQ, Huq F

Anticancer Res, 2013 Oct;33(10):4365-71.
PMID: 24123004

Andrographolide (Andro) is a diterpenoid that is isolated from Andrographis paniculata and reported to be active against several cancer cell lines. However, few in-depth studies have been carried out on its effects on ovarian cancer cell lines alone or in combination with cisplatin (Cis), which is commonly used to treat ovarian cancer. The aim of this study was to determine the anti-proliferative and apoptotic effects of Andro administered alone and in combination with Cis in the ovarian A2780 and A2780(cisR) cancer cell lines using five different sequences of administration (Cis/Andro h): 0/0h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The results were evaluated in terms of medium-effect dose (Dm) and combination indices (CI) using the CalcuSyn software. Unlike Cis, whose activity was lower in the resistant A2780(cisR) cell line than in the parent A2780 cell line, Andro was found to be three times more active in the A2780(cisR) cell line as compared to that in A2780 cell line. Synergism was observed when Cis and Andro were administered using the sequences 0/4 h and 4/0 h. The percentage of apoptotic cell death was found to be greater for the 0/4 h combination of Andro and Cis as compared to those values from single-drug treatments. The results may be clinically significant if confirmed in vivo.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Targeting bladder cancer stem cells using Newcastle disease virus

Arcana Thirumorthy, De-Ming Chau, Khatijah Yusoff, Abhi Veerakumarasivam

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):24-24.
MyJurnal

Introduction: Bladder cancer is associated with high risk of tumour recurrence and therapeutic resistance. Cancer stem cells (CSC) within a particular tumour are postulated to drive tumorigenesis and influence tumour behaviour. Recent studies have shown that Newcastle disease virus (NDV) is able to selectively kill and exert a strong oncolytic effect against various cancer types. However little is known about the oncolytic effect of NDV against CSC. In this study, the oncolytic effect of NDV against putative bladder CSC was examined. Methods: Putative bladder CSC was selectively grown in the form of 3D-spheroids from six different bladder cancer cell lines. The spheroid cells were characterised for their stemness properties to ensure that these cells truly represent CSC. This was conducted via the analysis of CSC associated genes and cell surface markers expression. Subsequently, the oncolytic effect of the wild-type NDV-AF2240 strain against the bladder cancer spheroids was investigated. Results: All the spheroids expressed significantly high levels of CSC-associated genes. Flow-cytometry analysis revealed that the expression pattern of the CSC-associated surface markers was different in the spheroid cells; suggesting heterogeneity in the expression signatures of these cells. The infection of spheroids with NDV showed that the NDV was able to target bladder cancer spheroids but there was a spectrum of response across the different spheroids. Intriguingly, NDV was able to persistently infect bladder cancer spheroids that were not sensitive towards NDV infection as the presence of NDV viral genes were detected in the spheroid cells. The NDV persistently infected bladder cancer spheroids were resistant to superinfection and developed an antiviral state by expressing low levels of interferon-beta (IFN-b). NDV persistency of infection affects the process of epithelial to mesenchymal transition (EMT) of cancer cells as the spheroid forming ability of an established NDV persistently infected bladder cancer cell line, EJ28-PI was shown to be impaired. The EJ28-PI cells expressed significantly high levels of the EN2 gene. Knockdown of the EN2 expression reduced the viability of EJ28-PI cells; suggesting a role for EN2 in mediating NDV persistency of infection in cancer cells. Conclusion: Bladder CSC gene expression signatures influence the efficacy of NDV-mediated oncolysis. Our current work is focused on identifying genes and signalling pathways that influence NDV-mediated oncolysis us-ing whole-transcriptomic sequencing. The findings of this study can potentially be used to enhance the efficacy of NDV-mediated oncolysis and accelerate the translation of NDV as an oncotherapeutic agent in the clinic.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Emerging Pathogenic and Prognostic Significance of Paired Box 3 (PAX3) Protein in Adult Gliomas

Angelopoulou E, Paudel YN, Piperi C

Transl Oncol, 2019 Jul 25;12(10):1357-1363.
PMID: 31352198 DOI: 10.1016/j.tranon.2019.07.001

Gliomas present the most common type of brain tumors in adults, characterized by high morbidity and mortality. In search of potential molecular targets, members of paired box (PAX) family have been found expressed in neural crest cells, regulating their proliferation, apoptosis, migration and differentiation. Recently, PAX3 overexpression has been implicated in glioma tumorigenesis by enhancing proliferation, increasing invasiveness and inducing resistance to apoptosis of glioma cells, while maintaining brain glioma stem cells (BGSCs) stemness. Although the oncogenic potential of PAX3 in gliomas is still under investigation, experimental evidence suggests that PAX3 function is mainly mediated through the canonical and non-canonical Wnt signaling pathway as well as through its interaction with GFAP and p53 proteins. In addition, PAX3 may contribute to the chemoresistance of glioma cells and modulates the effectiveness of novel experimental therapies. Further evidence indicates that PAX3 may represent a novel diagnostic and prognostic biomarker for gliomas, facilitating personalized treatment. This review addresses the emerging role of PAX3 in glioma diagnosis, prognosis and treatment, aiming to shed more light on the underlying molecular mechanisms that could lead to more effective treatment approaches.

Matched MeSH terms: Drug Resistance, Neoplasm
Identification of differentially expressed circular RNAs in chemoresistant colorectal cancer

Abu N, Hon KW, Jeyaraman S, Yahaya A, Abdullah NM, Mustangin M, et al.

Epigenomics, 2019 06;11(8):875-884.
PMID: 31020847 DOI: 10.2217/epi-2019-0042

Aim: Chemoresistance in colorectal cancer (CRC) has become a burden in treating the disease effectively. Circular RNAs (circRNAs) are a type of noncoding RNA that were found to be important in cellular homeostasis. The involvement of circRNAs in relation to chemoresistance in other types of cancers has also been reported. This study aims to identify the differentially expressed circRNAs between chemoresistant and chemosensitive CRC cells. Materials & methods: We developed a chemoresistant cell line model and profiled the circRNAs via microarray. We further validated the expression of two circRNAs in 25 formalin-fixed paraffin-embedded (FFPE) tissue specimens (13 nonresponders and 12 responders) via quantitative polymerase chain reaction (qPCR). Results & conclusion: We found that there were 773 upregulated and 732 downregulated circRNAs between the chemoresistant and chemosensitive HCT-116 cells. We found that hsa_circ_32883 could be a promising biotarget.

Matched MeSH terms: Drug Resistance, Neoplasm
Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases

Parama D, Boruah M, Yachna K, Rana V, Banik K, Harsha C, et al.

Life Sci, 2020 Nov 01;260:118182.
PMID: 32781063 DOI: 10.1016/j.lfs.2020.118182

BACKGROUND: Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more.
AIM: To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases.
METHOD: A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs.
KEY FINDINGS: The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties.
SIGNIFICANCE: Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.

Matched MeSH terms: Drug Resistance, Neoplasm
Reversal of multidrug resistance (MDR) by aspidofractinine-type indole alkaloids

Kam TS, Subramaniam G, Sim KM, Yoganathan K, Koyano T, Toyoshima M, et al.

Bioorg Med Chem Lett, 1998 Oct 06;8(19):2769-72.
PMID: 9873619

A series of indole alkaloids of the aspidofractinine-type was assessed for their potential in reversing MDR in vincristine-resistant KB cells. Of the compounds tested, kopsiflorine, kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine A and N-methoxycarbonyl-11,12-methylenedioxy-delta 16,17-kopsinine were found to show appreciable activity.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Identification of Predictive DNA Methylation Biomarkers for Chemotherapy Response in Colorectal Cancer

Baharudin R, Ab Mutalib NS, Othman SN, Sagap I, Rose IM, Mohd Mokhtar N, et al.

Front Pharmacol, 2017;8:47.
PMID: 28243201 DOI: 10.3389/fphar.2017.00047

Resistance to 5-Fluorouracil (5-FU) is a major obstacle to the successful treatment of colorectal cancer (CRC) and posed an increased risk of recurrence. DNA methylation has been suggested as one of the underlying mechanisms for recurrent disease and its contribution to the development of drug resistance remains to be clarified. This study aimed to determine the methylation phenotype in CRC for identification of predictive markers for chemotherapy response. We performed DNA methylation profiling on 43 non-recurrent and five recurrent CRC patients using the Illumina Infinium HumanMethylation450 Beadchip assay. In addition, CRC cells with different genetic backgrounds, response to 5-FU and global methylation levels (HT29 and SW48) were treated with 5-FU and DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC). The singular and combined effects of these two drug classes on cell viability and global methylation profiles were investigated. Our genome-wide methylation study on the clinical specimens showed that recurrent CRCs exhibited higher methylation levels compared to non-recurrent CRCs. We identified 4787 significantly differentially methylated genes (P < 0.05); 3112 genes were hyper- while 1675 genes were hypomethylated in the recurrent group compared to the non-recurrent. Fifty eight and 47 of the significantly hypermethylated and hypomethylated genes have an absolute recurrent/non-recurrent methylation difference of ≥20%. Most of the hypermethylated genes were involved in the MAPK signaling pathway which is a key regulator for apoptosis while the hypomethylated genes were involved in the PI3K-AKT signaling pathway and proliferation process. We also demonstrate that 5-azadC treatment enhanced response to 5-FU which resulted in significant growth inhibition compared to 5-FU alone in hypermethylated cell lines SW48. In conclusion, we found the evidence of five potentially biologically important genes in recurrent CRCs that could possibly serve as a new potential therapeutic targets for patients with chemoresistance. We postulate that aberrant methylation of CCNEI, CCNDBP1, PON3, DDX43, and CHL1 in CRC might be associated with the recurrence of CRC and 5-azadC-mediated restoration of 5-FU sensitivity is mediated at least in part by MAPK signaling pathway.

Matched MeSH terms: Drug Resistance, Neoplasm
NOTCH1 Signaling Regulates Self-renewal and Platinum Chemoresistance of Cancer Stem-like Cells in Human Non-small Cell Lung Cancer

Zhang Y, Xu W, Guo H, Zhang Y, He Y, Lee SH, et al.

Cancer Res, 2017 Apr 17.
PMID: 28416482 DOI: 10.1158/0008-5472.CAN-16-1633

Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse and therapeutic resistance, but their specific pathogenic characters in many cancers including non-small cell lung cancer (NSCLC) have yet to be well defined. Here we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166(+)CD49f(hi)CD104(-)Lin(-) LCSC present in all human specimens of NSCLC examined, regardless of their histological subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a γ-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo Overall, our results define the pathogenic characters of a cancer stem-like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease.

Matched MeSH terms: Drug Resistance, Neoplasm
JNK signaling in cancer cell survival

Wu Q, Wu W, Fu B, Shi L, Wang X, Kuca K

Med Res Rev, 2019 11;39(6):2082-2104.
PMID: 30912203 DOI: 10.1002/med.21574

c-Jun N-terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor-β, toll-like receptors, interferon-γ, and autophagy, as well as compensatory JNK-dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK-mediated cancer cell survival. There is a focus on the specific "Yin and Yang" functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Clinical Theragnostic Potential of Diverse miRNA Expressions in Prostate Cancer: A Systematic Review and Meta-Analysis

Jayaraj R, Raymond G, Krishnan S, Tzou KS, Baxi S, Ram MR, et al.

Cancers (Basel), 2020 May 09;12(5).
PMID: 32397507 DOI: 10.3390/cancers12051199

Background: Prostate cancer (PrC) is the second-most frequent cancer in men, its incidence is emerging globally and is the fifth leading cause of death worldwide. While diagnosis and prognosis of PrC have been studied well, the associated therapeutic biomarkers have not yet been investigated comprehensively. This systematic review and meta-analysis aim to evaluate the theragnostic effects of microRNA expressions on chemoresistance in prostate cancer and to analyse the utility of miRNAs as clinical theragnostic biomarkers. Methods: A systematic literature search for studies reporting miRNA expressions and their role in chemoresistance in PrC published until 2018 was collected from bibliographic databases. The evaluation of data was performed as per PRISMA guidelines for systematic review and meta-analysis. Meta-analysis was performed using a random-effects model using Comprehensive Meta-Analysis (CMA) software. Heterogeneity between studies was analysed using Cochran's Q test, I2 and the Tau statistic. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS) for the methodological assessment of cohort studies. Publication bias was assessed using Egger's bias indicator test, Orwin and classic fail-safe N test, Begg and Mazumdar rank collection test, and Duval and Tweedie's trim and fill methods. Findings: Out of 2909 studies retrieved, 79 studies were shortlisted and reviewed. A total of 17 studies met our eligibility criteria, from which 779 PrC patients and 17 chemotherapy drugs were examined, including docetaxel and paclitaxel. The majority of the drug regulatory genes reported were involved in cell survival, angiogenesis and cell proliferation pathways. We studied 42 miRNAs across all studies, out of which two miRNAs were found to be influencing chemosensitivity, while 21 were involved in chemoresistance. However, the remaining 19 miRNAs did not appear to have any theragnostic effects. Besides, the prognostic impact of the miRNAs was evaluated and had a pooled HR value of 1.960 with 95% CI (1.377-2.791). Interpretation: The observation of the current study depicts the significance of miRNA expression as a theragnostic biomarker in medical oncology. This review suggests the involvement of specific miRNAs as predictors of chemoresistance and sensitivity in PrC. Hence, the current systematic review and meta-analysis provide insight on the use of miRNA as PrC biomarkers, which can be harnessed as molecular candidates for therapeutic targeting.

Matched MeSH terms: Drug Resistance, Neoplasm
Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer

Dzul Keflee R, Leong KH, Ogawa S, Bignon J, Chan MC, Kong KW

Biochem Pharmacol, 2022 Nov;205:115262.
PMID: 36191627 DOI: 10.1016/j.bcp.2022.115262

The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanisms of resistance towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever-evolving and adaptive nature of NSCLC.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Blockade of c-Met-Mediated Signaling Pathways by E7050 Suppresses Growth and Promotes Apoptosis in Multidrug-Resistant Human Uterine Sarcoma Cells

Huang TT, Chen CM, Lan YW, Lin SS, Choo KB, Chong KY

Int J Mol Sci, 2022 Nov 28;23(23).
PMID: 36499211 DOI: 10.3390/ijms232314884

E7050 is a potent inhibitor of c-Met receptor tyrosine kinase and has potential for cancer therapy. However, the underlying molecular mechanism involved in the anti-cancer property of E7050 has not been fully elucidated. The main objective of this study was to investigate the anti-tumor activity of E7050 in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells in vitro and in vivo, and to define its mechanisms. Our results revealed that E7050 reduced cell viability of MES-SA/Dx5 cells, which was associated with the induction of apoptosis and S phase cell cycle arrest. Additionally, E7050 treatment significantly upregulated the expression of Bax, cleaved PARP, cleaved caspase-3, p21, p53 and cyclin D1, while it downregulated the expression of survivin and cyclin A. On the other hand, the mechanistic study demonstrated that E7050 inhibited the phosphorylation of c-Met, Src, Akt and p38 in HGF-stimulated MES-SA/Dx5 cells. Further in vivo experiments showed that treatment of athymic nude mice carrying MES-SA/Dx5 xenograft tumors with E7050 remarkably suppressed tumor growth. E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma.

Matched MeSH terms: Drug Resistance, Neoplasm
Fulltext Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development

Madden SF, Cremona M, Farrelly AM, Low WH, McBryan J

Cancer Gene Ther, 2023 Feb;30(2):324-334.
PMID: 36266450 DOI: 10.1038/s41417-022-00548-0

To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.

Matched MeSH terms: Drug Resistance, Neoplasm

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