New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

Gatti, Laura; Cassinelli, Giuliana; Zaffaroni, Nadia; Lanzi, Cinzia; Perego, Paola

doi:10.1016/j.drup.2015.04.001

Cited by 53 publications

(51 citation statements)

References 145 publications

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“…Classical anticancer drugs inhibit cell replication and transcription through the direct or indirect interaction with DNA, and induce mutagenic, cytotoxic, genotoxic and carcinogenic effects (Chen, Chang, & Cheng, ; Fonseca et al, ; Lin et al, ). For example the platinum‐based drugs such as cisplatin and other square‐planar platinum analogs (carboplatin and oxaliplatin), which, despite their success as chemotherapeutics, cause renal failure and nephrotoxicity, peripheral neuropathy, hepatic toxicity, myelotoxicity, gastrointestinal toxicity, ototoxicity, hematological toxicity and drug resistance (Bergamo et al, ; Brock et al, ; Gatti, Cassinelli, Zaffaroni, Lanzi, & Perego, ; Grozav et al, ; Keppler, Berger, & Heim, ; Mengoli, Parmeggiani, Mengoli, Grinzi, & Tolomelli, ; Muggia, ; Quasthoff & Hartung, ). Treatment with these drugs is therefore limited.…”

Section: Introductionmentioning

confidence: 99%

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Carnizello

Alves

Pereira

et al. 2018

J of Applied Toxicology

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Considering the promising previous results of ct‐[RuCl(CO)(dppb)(bipy)]PF6 (where dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine) as an antitumor agent, novel biological assays evaluating its toxicogenic potential were performed. The genotoxicity of the compound was evaluated by the in vitro micronucleus test (V79, Chinese hamster lung fibroblasts; HepG2, hepatocellular carcinoma cells), in vivo bone marrow micronucleus test and comet assay in hepatocytes (Swiss mice). The animals were treated with 0.63, 1.25, 2.5 and 5.0 mg/kg body weight (bw) of the compound. Negative (water) and positive (cisplatin, 1.5 mg/kg bw; methyl methanesulfonate, 40 mg/kg bw) controls were included. The parameters considered in the comet assay were the percentage of tail DNA, tail moment and tail length. The results of the in vitro micronucleus tests showed the absence of genotoxicity in V79 cells, while the compound was genotoxic in HepG2 cells at a concentration of 1.25 μm. In the in vivo micronucleus test, the compound was not genotoxic at the different doses evaluated. In the comet assay, only the dose of 5.0 mg/kg bw resulted in a significant increase in the frequency of DNA damage in hepatocytes when compared to the negative control. The genotoxic effect observed in HepG2 cells and in the liver comet assay indicates that the compound was metabolized by hepatic cells.

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Section: Introductionmentioning

confidence: 99%

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Carnizello

Alves

Pereira

et al. 2018

J of Applied Toxicology

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“…Recently, investigators have paid more attention to these "nonnuclear" effects and the molecular pathways that are involved in the cell survival and apoptotic escape. (3) Our previous study showed that sequestosome-1 (p62/SQSTM1) was highly expressed in cisplatin-resistant ovarian cancer cells. Furthermore, resistance to Pt was removed when we inhibited the p62 expression with the siRNA.…”

mentioning

confidence: 98%

“…Since the 1970s, tolerance to Pt has been blamed on effects unrelated to DNA damage. Recently, investigators have paid more attention to these “non‐nuclear” effects and the molecular pathways that are involved in the cell survival and apoptotic escape . Our previous study showed that sequestosome‐1 (p62/SQSTM1) was highly expressed in cisplatin‐resistant ovarian cancer cells.…”

mentioning

confidence: 99%

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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Platinum‐based therapeutic strategies have been widely used in ovarian cancer treatment. However, drug resistance has greatly limited therapeutic efficacy. Recently, tolerance to cisplatin has been attributed to other factors unrelated to DNA. p62 (also known as SQSTM1) functions as a multifunctional hub participating in tumorigenesis and may be a therapeutic target. Our previous study showed that p62 was overexpressed in drug‐resistant ovarian epithelial carcinoma and its inhibition increased the sensitivity to cisplatin. In this study, we demonstrate that the activity of the NF‐κB signaling pathway and K63‐linked ubiquitination of RIP1 was higher in cisplatin‐resistant ovarian (SKOV3/DDP) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using siRNA. Furthermore, deletion of the ZZ domain of p62 that interacts with RIP1 in SKOV3 cells markedly decreased K63‐linked ubiquitination of RIP1 and inhibited the activation of the NF‐κB signaling pathway. Moreover, loss of the ZZ domain from p62 led to poor proliferative capacity and high levels of apoptosis in SKOV3 cells and made them more sensitive to cisplatin treatment. Collectively, we provide evidence that p62 is implicated in the activation of NF‐κB signaling that is partly dependent on RIP1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.

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“…The cytotoxicity of these compounds is due to the interaction with DNA and the formation of DNA-platinum adducts, with the subsequent induction of apoptosis [3]. Recently reviewed results also strongly suggest more complex mechanisms involved in this cytotoxicity, such as the interaction with mitochondria and with the immunologic tumour environment [4]. Several resistance mechanisms have been proposed to be involved in a decreased clinical response to platinum derivatives, such as modified expression of membrane copper transporters [5], increased inactivation of intracellular platinum derivatives by glutathione [6], defects in the apoptotic machinery [7] or increased repair activity on the DNA adducts [8,9].…”

Section: Introductionmentioning

confidence: 99%

Unexpected Growth-Promoting Effect of Oxaliplatin in Excision Repair Cross-Complementation Group 1 Transfected Human Colon Cancer Cells

et al. 2018

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The nucleotide excision repair protein excision repair cross-complementation group 1 (ERCC1) has been repeatedly shown to be involved in the sensitivity of cancer cells to platinum derivatives. In order to better understand this process, we transfected HCT-116 cells with a plasmid encoding ERCC1 and studied their in vitro and in vivo behaviour. No main differences were observed for sensitivity to platinum drugs, DNA repair capacity and clonogenicity in vitro. However, ERCC1-transfected HCT-116 cells showed paradoxical behaviour in vivo with increased growth in mice treated with oxaliplatin as compared to untreated mice. The Trop2 protein was identified as being potentially involved in the underlying mechanism for these observations, as it was overexpressed in transfected cells. Our results suggest complex regulation of signalling in cancer cells exposed to cancer drugs.

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New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

Cited by 53 publications

References 145 publications

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Unexpected Growth-Promoting Effect of Oxaliplatin in Excision Repair Cross-Complementation Group 1 Transfected Human Colon Cancer Cells

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New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

Cited by 53 publications

References 145 publications

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Unexpected Growth-Promoting Effect of Oxaliplatin in Excision Repair Cross-Complementation Group 1 Transfected Human Colon Cancer Cells

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Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays