Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics

Abstract

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice

“…This result is in agreement with previously reported data on the mode of action of this polynuclear agent—Pd 2 Spm is able to bind to DNA via unconventional, long-range crosslinks, which are more deleterious than conventional interactions (e.g., cisplatin-prompted), particularly towards fast-growing malignant cells [ 17 , 22 , 23 ]. A similar discrepancy between desired pharmacologic effects and cellular uptake has been recently reported for conventional Pt-based agents—cisplatin, carboplatin and oxaliplatin [ 5 ]. This study by Schoch and co-workers (2020) showed that carboplatin shares a mechanism of action with cisplatin, while oxaliplatin acts differently: the former led to identical DNA lesions (and a comparable gene response), and the latter exhibited similar cytotoxicity to cisplatin, despite its lower intracellular accumulation [ 5 ].…”

“…A similar discrepancy between desired pharmacologic effects and cellular uptake has been recently reported for conventional Pt-based agents—cisplatin, carboplatin and oxaliplatin [ 5 ]. This study by Schoch and co-workers (2020) showed that carboplatin shares a mechanism of action with cisplatin, while oxaliplatin acts differently: the former led to identical DNA lesions (and a comparable gene response), and the latter exhibited similar cytotoxicity to cisplatin, despite its lower intracellular accumulation [ 5 ]. Therefore, since Pd 2 Spm showed linear accumulation in breast cancer cells coupled to favorable pharmacokinetic and biodistribution properties, this study provides an encouraging basis for further in vivo studies focused on the anticancer properties of Pd 2 Spm.…”

“…Oxaliplatin ( Figure 1 c) is a 3rd generation platinum analog with a diaminocyclohexane ligand that significantly reduces its toxicity and glutathione-mediated acquired tumor cell resistance [ 4 ]. Although oxaliplatin is less reactive towards DNA than cisplatin, it was demonstrated in vitro that its crosslinks appear to be more damaging [ 5 ]. Currently, oxaliplatin in combination with 5-fluorouracil is approved for the treatment of advanced colorectal cancer.…”

Platinum Complexes in Colorectal Cancer and Other Solid Tumors

“…The activity of oxaliplatin is primarily a result of induced DNA lesions, but non-DNA targets may also contribute to its toxicity [ 130 ]. We and others observed that oxaliplatin induced fewer DNA platination damage than cisplatin, but it induced cell death to a comparable extent indicating that the damage has a higher impact [ 127 , 131 ]. Both cisplatin and oxaliplatin are active by the formation of DNA crosslinks, but oxaliplatin forms lesions on DNA with structures distinct to cisplatin lesions leading to a different gene expression profile and different modes of action [ 131 , 132 ].…”

“…We and others observed that oxaliplatin induced fewer DNA platination damage than cisplatin, but it induced cell death to a comparable extent indicating that the damage has a higher impact [ 127 , 131 ]. Both cisplatin and oxaliplatin are active by the formation of DNA crosslinks, but oxaliplatin forms lesions on DNA with structures distinct to cisplatin lesions leading to a different gene expression profile and different modes of action [ 131 , 132 ]. In response to oxaliplatin DNA damage, cell death is induced, which is mainly executed by the intrinsic apoptosis pathway, mediated by translocation of BAX to the mitochondria followed by cytochrome C release into the cytoplasm and activation of caspase 3 [ 133 ].…”