Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

Shen, Donglai; Pouliot, Lynn M.; Hall, Matthew D.; Gottesman, Michael M.

doi:10.1124/pr.111.005637

Cited by 764 publications

(686 citation statements)

References 139 publications

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“…CIS and related drugs (e.g., oxaliplatin and carboplatin) are widely prescribed in the clinic as antitumor drugs. Despite the importance of these drugs in clinical practice, several drawbacks have been observed since the discovery of CIS and the later development of second-and third-generation platinum compounds (8).…”

Section: Introductionmentioning

confidence: 99%

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.

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Section: Introductionmentioning

confidence: 99%

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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“…[1][2][3][4][5][6] It binds to DNA, forming inter-and intrastrand cross-links, resulting in defective DNA templates and the arrest of DNA synthesis in rapidly dividing cancer cells. 7,8) The major limitation of cisplatin chemotherapy is the development of dose-dependent nephrotoxicity in about 30% of patients. 9) As a major site for drug filtration, concentration, and excretion, renal tissues and cells are exposed to toxic concentrations of cisplatin during cancer therapy.…”

mentioning

confidence: 99%

Cisplatin Binding and Inactivation of Mitochondrial Glutamate Oxaloacetate Transaminase in Cisplatin-Induced Rat Nephrotoxicity

Ozaki

Ishiguro

Itoh

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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“…However, the major drawback of this current strategy is the lack of tumor cell specificity resulting in a multitude of unwanted side effects due to their cytotoxic effects on nontumor cells. Besides, some patients eventually develop resistance to cisplatin, greatly limiting its effectiveness (22,37,38). Therefore, there is an urgent need for the development of more novel and better molecular-based therapeutics in HPV16/18-associated cervical cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Targeted Silencing of MLL5β Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers

Nin¹,

Yew²,

Tay³

et al. 2014

Molecular Cancer Therapeutics

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We previously identified a novel MLL5 isoform, MLL5b, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAimediated silencing of MLL5b through the use of MLL5b-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5b silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model. This corresponded with the enhanced antitumor effects of MLL5b-siRNA compared with E6-or E7-siRNA single treatments. Significant reduction in tumor size after MLLb-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5b in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5b. We also identified MLL5b as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5b silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5b inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5b-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5b via the use of MLL5b-siRNA as a novel therapeutic strategy and propose that MLL5b-siRNA could be a viable alternative for cisplatin in the current cisplatin-based chemotherapeutics for HPV16/18-associated cervical cancers. Mol Cancer Ther; 13(11); 2572-82. Ó2014 AACR.

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Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

Cited by 764 publications

References 139 publications

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Cisplatin Binding and Inactivation of Mitochondrial Glutamate Oxaloacetate Transaminase in Cisplatin-Induced Rat Nephrotoxicity

Targeted Silencing of MLL5β Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers

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