Membrane drug transporters in cancer: From chemoresistance mechanism to therapeutic strategies

Chemoresistance is a multifactorial phenomenon and the primary cause to the ineffectiveness of oncotherapy and cancer recurrence. Membrane drug transporters are crucial for drug delivery and disposition in cancer cells. Changes in the expression and functionality of these transporters lead to decreased intracellular accumulation and reduced toxicity of antineoplastic drugs. As the mechanism has been better understood and genetic engineering technology progressed quickly in recent years, some novel targeting strategies have come to light. This article summarizes the regulatory mechanisms of membrane drug transporters and provides an extensive review of current approaches to address transporters-mediated chemoresistance. These strategies include the use of chemical inhibitors to block efflux transporters, the development of copper chelators to enhance platinum drug uptake, the delivery of genetic drugs to alter transporter expression, the regulation of transcription and post-translational modifications. Additionally, we provide information of the clinical trial performance of the related targeting strategies, along with the ongoing challenges. Even though some clinical trials failed due to unexpected side effects and limited therapeutic efficacy, the advent of targeting membrane drug transporters still presents a hopeful path for overcoming chemoresistance.