scholarly journals Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair–inhibiting (HYDRI) nanomedicine

2021 ◽  
Vol 7 (13) ◽  
pp. eabc5267
Author(s):  
Jing Chen ◽  
Xue Wang ◽  
Yuan Yuan ◽  
Haoting Chen ◽  
Lingpu Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Glucose Oxidase ◽  
Cancer Cells ◽  
Building Block ◽  
Cisplatin Resistance ◽  
Fitness Cost ◽  
Proof Of Concept ◽  
Patient Derived Xenograft ◽  
Tumor Drug Resistance

Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair–inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

scholarly journals Recent advances in the contribution of noncoding RNAs to cisplatin resistance in cervical cancer

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9234
Author(s):  
Xin Wen ◽  
Shui Liu ◽  
Jiyao Sheng ◽  
Manhua Cui
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Treatment Option ◽  
Disease Burden ◽  
Cisplatin Resistance ◽  
Noncoding Rnas ◽  
Mechanisms Of Action ◽  
Female Population ◽  
Cellular Processes

Cervical cancer (CC) remains a major disease burden on the female population worldwide. Chemotherapy with cisplatin (cis-diamminedichloroplatinum (II); CDDP) and related drugs are the main treatment option for CC; however, their efficacy is limited by the development of drug resistance. Noncoding RNAs (ncRNAs) have been found to play critical roles in numerous physiological and pathological cellular processes, including drug resistance of cancer cells. In this review, we describe some of the ncRNAs, including miRNAs, lncRNAs and circRNAs, that are involved in the sensitivity/resistance of CC to CDDP-based chemotherapy and discuss their mechanisms of action. We also describe some ncRNAs that could be therapeutic targets to improve the sensitivity of CC to CDDP-based chemotherapy.

scholarly journals A Simple Three-Dimensional In Vitro Culture Mimicking the In Vivo-Like Cell Behavior of Bladder Patient-Derived Xenograft Models

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1304
Author(s):  
Robson Amaral ◽  
Maike Zimmermann ◽  
Ai-Hong Ma ◽  
Hongyong Zhang ◽  
Kamilla Swiech ◽  
...  
Keyword(s):  
Drug Resistance ◽  
In Vitro Culture ◽  
Cancer Cells ◽  
Low Cost ◽  
Maintenance Cost ◽  
Tumor Spheroids ◽  
Patient Derived Xenograft ◽  
Pdx Models

Patient-derived xenograft (PDX) models allow for personalized drug selection and the identification of drug resistance mechanisms in cancer cells. However, PDX models present technical disadvantages, such as long engraftment time, low success rate, and high maintenance cost. On the other hand, tumor spheroids are emerging as an in vitro alternative model that can maintain the phenotype of cancer cells long enough to perform all assays and predict a patient’s outcome. The present work aimed to describe a simple, reproducible, and low-cost 3D in vitro culture method to generate bladder tumor spheroids using human cells from PDX mice. Cancer cells from PDX BL0293 and BL0808 models, previously established from advanced bladder cancer, were cultured in 96-well round-bottom ultra-low attachment (ULA) plates with 5% Matrigel and generated regular and round-shaped spheroids (roundness > 0.8) with a diameter larger than 400 μm and a hypoxic core (a feature related to drug resistance in solid tumors). The responses of the tumor spheroids to the antineoplastic drugs cisplatin, gemcitabine, and their combination were similar to tumor responses in in vivo studies with PDX BL0293 and BL0808 mice. Therefore, the in vitro 3D model using PDX tumor spheroids appears as a valuable tool that may predict the outcome of in vivo drug-screening assays and represents a low-cost strategy for such purpose.

scholarly journals Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

Cancer ◽  
2019 ◽  
Vol 126 (4) ◽  
pp. 894-907 ◽  
Author(s):  
Janice M. Santiago‐O’Farrill ◽  
S. John Weroha ◽  
Xiaonan Hou ◽  
Ann L. Oberg ◽  
Ethan P. Heinzen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Adenosine Diphosphate ◽  
Ovarian Cancer Cells ◽  
Patient Derived Xenograft ◽  
Polymerase Inhibitors ◽  
Xenograft Models

scholarly journals Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells

2019 ◽  
Author(s):  
Shifeng Shi ◽  
Xin Huang ◽  
Xiao Ma ◽  
Xiaoyan Zhu ◽  
Qinxian Zhang
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Esophageal Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cisplatin Resistance ◽  
High Expression ◽  
Drug Resistant ◽  
Cellular Resistance ◽  
Esophageal Cancer Cells

AbstractPurposeChemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumor’s acquired drug resistance, the related action mechanism is still not explored specifically.MethodsTo elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.ResultsSmall RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-resistant cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine–cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin’s inhibition of the cell cycle of sensitive cells.ConclusionSensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.

scholarly journals DNA Repair Defects in Sarcomas

2020 ◽  
Author(s):  
Niknam Riyahi ◽  
M. Reza Saadatzadeh ◽  
Khadijeh Bijangi-Vishehsaraei ◽  
Farinaz Barghi ◽  
Pankita H. Pandya ◽  
...  
Keyword(s):  
Overall Survival ◽  
Drug Resistance ◽  
Dna Repair ◽  
Cancer Cells ◽  
Large Degree ◽  
Repair System ◽  
Repair Pathway ◽  
Cancer Aggressiveness ◽  
Repair Activity ◽  
Degree Of Heterogeneity

DNA repair pathway is considered to be one of the most important mechanisms that protect cells from intrinsic and extrinsic stresses. It has been established that DNA repair activity has a crucial role in the way that cancer cells respond to treatment. Sarcomas are a group of tumors with mesenchymal origin in which their association with DNA repair aberrations has been reported in numerous studies. Special attention has been focused on exploiting these alterations to improve the patient’s overall survival and overcome drug resistance in cancer. While there is a large degree of heterogeneity among different types of sarcomas, DNA repair alteration is found to be a common defect in the majority of patients. In this chapter, we will introduce and review some of the most important dysregulated components involved in the DNA repair system, and discuss their association with tumorigenesis, cancer aggressiveness, drug resistance, and overall prognosis in the patients with sarcomas.

scholarly journals LncRNA-MALAT1 mediates cisplatin resistance via miR-101-3p/VEGF-C pathway in bladder cancer

2019 ◽  
Author(s):  
Peihua Liu ◽  
Xiaozhou Li ◽  
Yu Cui ◽  
Jinbo Chen ◽  
Chao Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Drug Sensitivity ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Chemotherapeutic Drug ◽  
Lncrna Malat1 ◽  
Immortalized Cells ◽  
Standard Strategy

Abstract Cisplatin (CDDP)-based chemotherapy is a standard strategy for the clinical treatment of patients with bladder cancer (BC). However, the anti-tumor efficacy of cisplatin is affected by multiple chemoresistance with complex molecular mechanisms. Recent evidence highlights the crucial regulatory roles of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of cancers and development of drug resistance. However, the roles and underlying molecular mechanisms of MALAT1 in cisplatin resistance of the BC cells remain largely unclear. In this study, we firstly demonstrated that MALAT1 expression was up-regulated in the BC tissues compared to the normal adjacent tissues and elevated in the cancer cells compared to the epithelial immortalized cells. Secondly, we found that suppression of MALAT1 enhanced the chemotherapeutic drug sensitivity and inhibited the cisplatin resistance of the BC cells. Thirdly, we showed that MALAT1 affected the cisplatin resistance of the BC cells via regulating the miR-101-3p/VEGF-C pathway. In summary, this study demonstrates that MALAT1, miR-101-3p and VEGF-C form a regulatory axis to affect the chemo-resistance of BC cells to CDDP, and provides novel potential targets for treatment of BC.

scholarly journals Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

2020 ◽  
Vol 11 (15) ◽  
pp. 3829-3835 ◽  
Author(s):  
Shuren Zhang ◽  
Xuanmeng Zhong ◽  
Hao Yuan ◽  
Yan Guo ◽  
Dongfan Song ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
Repair Mechanism ◽  
Recombination Proteins

Platinum(iv) prodrugs targeting the DNA repair mechanism downregulate myeloid cell leukemia-1 (Mcl-1) and homologous recombination proteins (RAD51, BRCA2), thereby enhancing cytotoxicity against cisplatin-resistant cancer cells.

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