Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes

Mezencev, Roman; Matyunina, Lilya V.; Wagner, Geoffrey; McDonald, John F.

doi:10.1038/cgt.2016.71

Cited by 34 publications

(24 citation statements)

References 54 publications

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“…Inspection of the oxaliplatin repair slot blots such as in Figure 2A suggested uneven levels of initial damage among the cell lines. Oxaliplatin treatment is known to be influenced by factors such as drug influx, efflux, and neutralization (24)(25)(26). We therefore systematically compared the amount of initial damage incurred following treatment of each cell line with 200 uM oxaliplatin for 2 hours.…”

Section: Initial Damage Differs Significantly Between Sensitive and Rmentioning

confidence: 99%

Genome-wide single-nucleotide resolution of oxaliplatin–DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines

Vaughn

Selby

Yang

et al. 2020

Journal of Biological Chemistry

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Platinum-based chemotherapies, including oxaliplatin, are a mainstay in the management of solid tumors and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic, and approximately half of cancer patients have tumors that are either intrinsically resistant or develop resistance. Previous studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. Here, we aimed to better define the roles of nucleotide excision repair and DNA damage in platinum chemotherapy resistance by profiling DNA damage and repair efficiency in seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed DNA repair indirectly as toxicity and directly measured bulky adduct formation and removal from the genome by slot blot and repair capacity in an excision assay, and used excision repair sequencing (XR-seq) to map repair events genome-wide at single-nucleotide resolution. Using this combinatorial approach and proxies for oxaliplatin–DNA damage, we observed no significant differences in repair efficiency that could explain the relative sensitivities and chemotherapy resistances of these cell lines. In contrast, the levels of oxaliplatin-induced DNA damage were significantly lower in the resistant cells, indicating that decreased damage formation, rather than increased damage repair, is a major determinant of oxaliplatin resistance in these cell lines. XR-seq–based analysis of gene expression revealed up-regulation of membrane transport pathways in the resistant cells, and these pathways may contribute to resistance. In conclusion, additional research is needed to characterize the factors mitigating cellular DNA damage formation by platinum compounds.

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Section: Initial Damage Differs Significantly Between Sensitive and Rmentioning

confidence: 99%

Genome-wide single-nucleotide resolution of oxaliplatin–DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines

Vaughn

Selby

Yang

et al. 2020

Journal of Biological Chemistry

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“…On the other hand, cisplatin resistance in different pancreatic cancer cells was found to display significant differences in gene expression profiles (Mezencev et al, 2016). Miller et al reported that drug resistance in pancreatic cancer was associated with the presence of multidrug resistance-associated protein (MRP) (Miller et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…This is due to lack of diagnosis at an early stage of tumor development, ineffective therapy, its highly invasive and metastatic nature, and development of chemoresistance (Siegel et al, 2019). Drug resistance is a major reason for the inadequate efficacy of most pancreatic cancer therapies (Long et al, 2011;Mezencev et al, 2016). Cis-diamminedichloroplatinum (II), or cisplatin, a commonly used platinum-based anticancer drug for a wide range of solid tumors, is effective alone (Mezencev et al, 2016) or in combination with other chemotherapy drugs for the treatment of advanced or metastatic pancreatic cancer (Gresham et al, 2014;Ramfidis et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Drug resistance is a major reason for the inadequate efficacy of most pancreatic cancer therapies (Long et al, 2011;Mezencev et al, 2016). Cis-diamminedichloroplatinum (II), or cisplatin, a commonly used platinum-based anticancer drug for a wide range of solid tumors, is effective alone (Mezencev et al, 2016) or in combination with other chemotherapy drugs for the treatment of advanced or metastatic pancreatic cancer (Gresham et al, 2014;Ramfidis et al, 2014). Although cisplatin displays a broad spectrum of anticancer activity via multiple mechanisms, its clinical effectiveness is often limited due to chemoresistance and adverse side effects, especially peripheral sensory neurotoxicity (Florea and Büsselberg, 2011;Argyriou et al, 2014;Avan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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αvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model

Sudha

et al. 2020

Front. Pharmacol.

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Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether avb3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1b, IL-6, IL-10, and TNF-a from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of proinflammatory cytokines IL-1b, IL-6, and TNF-a and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatintreated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kB may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.

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“…A major difficulty in understanding drug resistance is that the molecular mechanisms that underpin it are complex and multifactorial . Indeed, resistance can arise via alterations in many different cellular processes, and the cause of resistance in one individual may not be the same as in another.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

2017

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Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises are multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long noncoding RNA, and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. While further characterization of the vesiculome and the mechanisms of EV function are still required, EVs offer an exciting opportunity in the fight against cancer.

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Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes

Cited by 34 publications

References 54 publications

Genome-wide single-nucleotide resolution of oxaliplatin–DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines

Genome-wide single-nucleotide resolution of oxaliplatin–DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines

αvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

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