First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

Abstract

Tumors include a heterogeneous population, of which a small proportion includes drug-resistant cancer (stem) cells. In drug-sensitive cancer populations, first-line chemotherapy reduces tumor volume via apoptosis. However, it stimulates drug-resistant cancer populations and finally results in tumor recurrence. Recurrent tumors are unresponsive to chemotherapeutic drugs and are primarily drug-resistant cancers. Therefore, increased apoptosis in drug-resistant cancer cells in heterogeneous populations is important in first-line chemotherapeutic treatments. The overexpression of ABCB1 (or P-gp) on cell membranes is an important characteristic of drug-resistant cancer cells; therefore, first-line combination treatments with P-gp inhibitors could delay tumor recurrence. Low doses of bipolar drugs showed P-gp inhibitory activity, and their use as a combined therapy sensitized drug-resistant cancer cells. FDA-approved bipolar drugs have been used in clinics for a long period of time, and their toxicities are well reported. They can be easily applied as first-line combination treatments for targeting resistant cancer populations. To apply bipolar drugs faster in first-line combination treatments, knowledge of their complete information is crucial. This review discusses the use of low-dose bipolar drugs in sensitizing ABCB1-overexpressing, drug-resistant cancers. We believe that this review will contribute to facilitating first-line combination treatments with low-dose bipolar drugs for targeting drug-resistant cancer populations. In addition, our findings may aid further investigations into targeting drug-resistant cancer populations with low-dose bipolar drugs.