Cisplatin: mode of cytotoxic action and molecular basis of resistance

Siddik, Zahid H.

doi:10.1038/sj.onc.1206933

Cited by 2,919 publications

(2,646 citation statements)

References 169 publications

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“…A high accumulation of platinum-DNA adducts has been observed in the nuclei of marginal cells of the stria vascularis, but not in OHCs that have been discussed as the main target of cisplatin-induced cell damage (Thomas et al, 2006). The augmented adduct levels in the nuclei of marginal cells are not caused by their inability to repair such DNA lesions (Siddik, 2003). When disregarding the impact of repair mechanisms, the level of DNA platination products is directly linked to the intracellular concentration, which can be increased by both excessive influx and decreased export.…”

Section: Discussionmentioning

confidence: 98%

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

García-Berrocal

Nevado

Ramírez‐Camacho

et al. 2007

British J Pharmacology

103

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Background and purpose: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg -1 body weight). Experimental approach: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. Key results: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. Conclusions and implications: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.

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Section: Discussionmentioning

confidence: 98%

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

García-Berrocal

Nevado

Ramírez‐Camacho

et al. 2007

British J Pharmacology

103

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“…[36][37][38][39] Indeed, native or acquired resistance to cisplatin can occur in cancer cells and MT overexpression is often part of this multi-factorial resistance. [36][37][38][39] Clearly, overexpression of MT reduces many of the subchronic toxic effects of cisplatin in rodents, 17,19,40 including DNA damage, 21 which is the suspected therapeutic mode of action for cisplatin. 37 Conversely, MT deficiency enhances subchronic 18,20 or chronic (present work) cisplatin toxicity in rodents.…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38][39] Clearly, overexpression of MT reduces many of the subchronic toxic effects of cisplatin in rodents, 17,19,40 including DNA damage, 21 which is the suspected therapeutic mode of action for cisplatin. 37 Conversely, MT deficiency enhances subchronic 18,20 or chronic (present work) cisplatin toxicity in rodents. Based on the results of our present study, however, one of the characteristics that might make an initial tumor sensitive to cisplatin (i.e., low MT) may well predispose a host tissue to a second tumor as a delayed toxic effect.…”

Section: Discussionmentioning

confidence: 99%

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

Waalkes

Liu

Kasprzak

et al. 2006

Intl Journal of Cancer

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Metallothionein (MT) is a high-affinity metal binding protein thought to mitigate the toxicity of various metals. Cisplatin is a widely used cancer chemotherapeutic that is a rodent carcinogen and may have carcinogenic potential in humans. MT seems to reduce cisplatin toxicity by binding the metal compound but how MT deficiency might impact the carcinogenic effects of cisplatin is unknown. Thus, groups (n 5 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of cisplatin (5 or 10 mg/kg, i.p.), or left untreated (control) and observed over the next 104 weeks. The doses of cisplatin used equate to only a fraction of the total dose used typically in clinical settings. In cisplatin-treated MT-null mice, a dose-related increase in hepatocellular carcinoma (HCC) occurred (control, 0%; 5 mg/kg, 17%; 10 mg/kg, 36%) that was not seen in WT mice. Similarly, liver carcinoma multiplicity (HCC/liver) was increased markedly by cisplatin but only in MT-null mice, indicating the formation of multiple primaries in MT deficient mice. Harderian gland carcinoma incidence was also increased by cisplatin treatment in MT-null mice but not WT mice. Our results indicate that MT-null mice are hypersusceptible to the hepatocarcinogenic effects of cisplatin, and poor MT expression may be a predisposing factor for cisplatin-induced secondary tumors after chemotherapy. ' 2006 Wiley-Liss, Inc.Key words: cisplatin; carcinogenesis; mice; metallothionein To kill cancer cells, chemotherapeutic agents are often used at toxic levels. One long-term manifestation of these toxic effects could be secondary tumor formation. 1 As cancer survival improves because of more effective treatments, secondary, iatrogenic tumors arising from the initial therapeutic intervention will become an increasing issue 1 and knowledge of factors that predispose patients to such tumors could have important clinical applications. For instance, although cis-diamminedichloroplatinum(II) (cisplatin) is a widely used and very effective cancer chemotherapeutic, it can have limiting side effects and is considered probably carcinogenic in humans. 2,3 There are many case reports of secondary tumors developing in cancer patients that had received cisplatin for an initial malignancy, although this metallochemotherapeutic is used typically in combination with other chemical or physical treatments making etiologic linkage to any one component of the combination difficult. 2,3 Cisplatin is a complete carcinogen in rats or mice, however, inducing malignant tumors of the hematopoietic system and benign tumors of the liver. [4][5][6][7] Similarly, cisplatin will enhance the incidence or increase the multiplicity of benign lung tumors in strain A mice. [8][9][10] The platinum drug is also an effective initiator of renal and dermal cancers in rodents. 4,5,10,11 Metallothionein (MT) is a multi-functional, ubiquitously expressed, low-molecular-weight, metal-binding protein. [12][13][14][15] MT is distinctive in having numerous cysteines th...

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“…This study intends to understand the underlying mechanism of individual differences in response to cisplatin. Cisplatin is widely used to treat a variety of cancers and kills cells by directly or indirectly inducing apoptosis, DNA damage, and cell cycle arrest (Siddik, 2003). However, individual differences in response to cisplatin are an obstacle to effective cancer treatment.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the performance of the patient–drug two‐layer integrated network was generalizable and could be used to estimate drug responses effectively. Furthermore, we focused on cisplatin which is widely used to treat a variety of cancers and kills cells by directly or indirectly inducing apoptosis, DNA damage, and cell cycle arrest (Siddik, 2003). However, individual differences in response to cisplatin are an obstacle to effective cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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Cisplatin: mode of cytotoxic action and molecular basis of resistance

Cited by 2,919 publications

References 169 publications

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

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