Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it

Abstract

Regardless of continuous research to develop effective chemotherapies and improve patient’s prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem.

Keywords:

• Cancer
• DMEs
• drug resistance
• ALDH
• CYP450
• NQO1
• DPD
• GST
• UGT

Acknowledgment

The authors thank Dr. RajagopalareddySaleem, Assistant professor, School of computational Sciences, Central University of Bathinda, Bathinda, Punjab, India for his support.

Disclosure statement

There is no potential conflict of interest to report.

Additional information

Funding

Author(s) would like to thank Indian Council of Medical Research (ICMR) New Delhi for providing Senior Research Fellowship (SRF); Award no. ISRM/11(61)/2017.