New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment

Abstract

Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance.

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

“…Furthermore, recurrence of ovarian cancer is up to 75% and the recurrent cancer can result in the acquisition of cisplatin resistance, as well [ 43 ]. Thus, cisplatin resistance is a limitation of cisplatin chemotherapy, since there are several molecular mechanisms leading to cisplatin resistance [ 45 , 46 , 47 ]. Among the mechanical reasons, previous studies showed that upregulation of FOXM1 induced cisplatin resistance in several cancer cells [ 48 , 49 , 50 ].…”

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…The appearance of drug resistances, issuing from acquired or intrinsic multiple genetic and epigenetic changes, has also limited the clinical use of platinum-derived drugs [ 8 ]. Platinum-based treatment efficiency is challenged by cross-resistance and multiple changes including a decreased accumulation of the drug, a reduction in DNA–drug adducts, a modification in cell survival gene expression, an alteration of DNA damage repair mechanisms, modifications of transporters, protein trafficking, and altered cell metabolism [ 9 , 10 , 11 , 12 , 13 , 14 ].…”

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

“…A decreased expression of the membrane copper transporter CTR1 or the organic cation transporter OCT2, as well as a high expression of the copper-exporting P-type ATPases, ATP7A and ATP7B, or the ATP-binding cassette multidrug transporter, MRP2, could lead to decreased intracellular levels of platinum drugs, thereby causing resistance. Furthermore, high expression levels of glutathione S-transferase, a detoxifying enzyme responsible for the formation of platinum-glutathione conjugates, would also facilitate resistance [52]. A combination of these already identified markers with differences in estrogen metabolism could allow a better prediction of platinum resistance in patients.…”