Is Autophagy Always a Barrier to Cisplatin Therapy?

Abstract

Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There has been increasing recognition of autophagy as a critical factor affecting tumor cell death and tumor chemoresistance. In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic.

Keywords: autophagy; chloroquine; cisplatin; p53; resistant.

Figure 1

Primary mechanisms of cisplatin resistance. (a) Decrease in DNA adduct levels. Inward transport: copper transporter 1 (CTR1) and organic cation transporters (OCTs). Outward transport: ATP-binding cassette (ABC) multidrug transporters (including the multidrug resistance proteins and multidrug resistance-associated protein families). ATP7A/B, which belongs to the copper-transporting P-type ATPase, is the response for delivering copper into the organelles and removing the excess copper out of cells. (b) DNA damage recognition defects and increased DNA damage tolerance. (c) Inhibition of apoptosis. (d) Induction of cytoprotective autophagy. APE1: apurinic/apyrimidinic endonuclease 1; ATM: ataxia telangiectasia mutated protein; ATR: ataxia telangiectasia and RAD3-related protein; AMBRA1: activating molecule in Beclin1-regulated autophagy.