Abstract
Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge for scientific research. Recent studies have brought to light the fundamental role of mitochondria in onset, progression, and metastasis of cancer, as well as its importance in the resistance to chemotherapy. The aim of this review is to give an overview of the current knowledge about the implication of mitochondria in cisplatin resistance and on the recent development in this research field. Recent studies have highlighted the role of mitochondrial DNA alterations in onset of resistance phenomena, being related both to redox balance alterations and to signal crosstalk with the nucleus, allowing a rewiring of cell metabolism. Moreover, an important role of the mitochondrial dynamics in the adaptation mechanism of cancer cells to challenging environment has been revealed. Giving bioenergetic plasticity to tumor cells, mitochondria allow cells to evade death pathways in stressful conditions, including chemotherapy. So far, even if the central role of mitochondria is recognized, little is known about the specific mechanisms implicated in the resistance. Nevertheless, mitochondria appear to be promising pharmacological targets for overcoming cisplatin resistance, but further studies are necessary.
Highlights
Cis-diamine-dichloroplatinum (II) is the most employed platinum-based compound and the first approved by FDA (Food and Drug Administration) in 1978 for the treatment of testicular and bladder cancer
Park et al have shown that hepatocarcinoma cells depleted from mitochondrial DNA (mtDNA) were less sensitive to ROS-inducing agents including doxorubicin, sorafenib, and CDDP [80]
Montopoli et al (2011) have demonstrated that in rho0 clones derived from ovarian cancer cells 2008 and C13, the potency of CDDP was significantly reduced in 2008-rho0 but not in C13-rho0 when compared to their parental line [82]
Summary
Cis-diamine-dichloroplatinum (II) (best known as cisplatin or CDDP) is the most employed platinum-based compound and the first approved by FDA (Food and Drug Administration) in 1978 for the treatment of testicular and bladder cancer. Researches highlight how the acquisition of resistance can be due to decrease in drug accumulation, which includes reduced uptake or increased efflux of the drugs, enhanced drug detoxification system due to high levels of scavengers such as glutathione/metallothioneins, increased tolerance to damaged DNA, increased DNA repair mechanisms or to a metabolic rewiring of the cells in order to elude cisplatin-induced death [11,12,13,14,15] These mechanisms are peculiar to each cancer cell line in such a way that a particular tumor may exhibit one, two or even all the above-mentioned resistance mechanisms [16]. The identification of different pathways and molecular targets may offer new perspective for overcoming resistance phenomena and to reduce the toxic effect of the platinum drugs [23]
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