Abstract
P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.
Highlights
Chemotherapy has been the mainstay of cancer treatment for several decades, and is still an indispensable treatment component in current standard of care
Several other proteins of the ATP-binding cassette (ABC) transporter family were identified that shared a common mechanism of conferring chemotherapy resistance by drug efflux [4]
P-gp is widely expressed in a variety of organs including the liver, kidney and gastrointestinal tract [6], and upregulation of p-gp is closely linked with increased chemoresistance in cancer [7]
Summary
Chemotherapy has been the mainstay of cancer treatment for several decades, and is still an indispensable treatment component in current standard of care. Earliest efforts of p-gp inhibitors in cancer included trials using verapamil [8] and cyclosporine [9] but they were unsuccessful and demonstrated many adverse effects [10]. In a randomized phase II clinical trial in patients diagnosed with small cell lung cancer receiving cyclophosphamide, doxorubicin, vincristine, and etoposide (CAVE), a daily dose of 480 mg was given in combination with chemotherapy, with hypotension as a dose limiting toxicity for verapamil [11].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
