Cisplatin resistance reversal by disulfiram and caffeine

Abstract

Therapy resistance and relapse are the major issues associated with the current management of cancer. Cancer stem cells (CSCs) have inbuilt mechanisms to develop resistance. The most commonly overexpressed markers of CSCs are aldehyde dehydrogenase (ALDH) enzymes and ATP-binding cassette transporters (e.g., ABCG2). Moreover, cells have the capability to induce checkpoint responses when exposed to genotoxic agents (i.e., chemotherapy or radiation therapy), causing arrest of cells cycle. Resistance followed by chemotherapy administration as observed clinically can be divided into two phases. The first phase involves conversion of actively dividing cells to a completely dormant stage where cells do not divide though remain metabolically active. This stage can be defined as therapy-induced senescence. At this stage, chemotherapeutic agents fail to produce desired effect because cells are not dividing. The second phase is conversion of these dormant cells to actively dividing cells after longer duration. These cells may be even more resistant than parent cells and hence, require higher concentration of chemotherapeutic agents to arrest cell division. Disulfiram, an antabuse drug, is reported to inhibit ALDH, efflux pump, and some other potential cellular targets in cancer cells. Caffeine is reported to inhibit the checkpoint responses that are responsible for development of senescence. Hence, both disulfiram and caffeine simultaneously can be used to target CSCs and senescent cells, which are major contributors of therapy resistance.