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.

Keywords: cisplatin; drug resistance; tumor microenvironment.

Figure 1

Schematic representation of intracellular mechanisms with an effect on the development of cisplatin resistance with clinical implications. Inside the tumor cell, decreased drug import, increased drug export, increased drug inactivation by detoxification enzymes, increased DNA damage repair, and inactivated cell death signaling are major mechanisms leading to cisplatin resistance. Interactions between a cell and its environmental components can also promote these internal mechanisms and subsequent cisplatin resistance.

Figure 2

Components of tumor microenvironment reported to affect cisplatin resistance. These components can contribute to cisplatin resistance through decreased drug delivery, increased acidity or shear stress, cell adhesion or cytokine-mediated drug resistance mechanisms, and immunosuppressive activity.