Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

Abstract

Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients’ responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent

“…The hosts themselves can play an important role in these therapeutic failures through a dysfunction of metabolic enzymes or overly high toxicity of the anticancer agent, thereby requiring discontinuation of treatment. This is the case with various drugs such as cisplatin (CDDP), which is a highly effective chemotherapeutic agent for a variety of cancers, including CRC, but causes more side effects including genotoxicity, nephrotoxicity, and acute myelotoxicity [4,5], and 5-fluorouracil , which can cause undesirable severe toxicities observed in 10-40% of patients (e.g., hematological, digestive, cardiac disorders, and mucositis) [6,7], subsequently limiting their use. The third factor that plays an important role is the cancer cell itself, which can, following chemotherapeutic treatment, initially develop or acquire resistance systems such as the overexpression of efflux transporters, the modulation of phase I and phase II enzymes, alterations in the cell death pathways, or alteration of the DNA-damage pathway, leading to the death of cancer cells [8,9].…”

LncRNA MIR4435-2HG mediates cisplatin resistance in HCT116 cells by regulating Nrf2 and HO-1

“…Cisplatin is thought to formulate the covalent adducts with some bases in the DNA, then could cure many testicular and some ovarian carcinomas [8,9].…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…From its first introduction in bedside oncology different mechanisms of action for CDDP have been described [267,268]. An almost completely disregarded issue in bedside oncology hs been the fact that CDDP can significantly modify the intracellular pH of cancer cells inducing cytoplasmatic acidification through a CDDP-mediated inhibition of H+ extrusion secondary to downregulation of NHE-1 [207,208,210,267] (Table 2).…”