A novel polymerase β inhibitor from phage displayed peptide library augments the anti-tumour effects of temozolomide on colorectal cancer

Abstract

The therapeutic efficacy of TMZ, a common used drug for chemotherapy, is limited by the resistance from colorectal cancer cells. Base excision repair (BER) pathway has been identified as one of the reasons for drug resistance. By blocking Polβ-dependent BER (Base Excision Repair) pathway, the efficacy of TMZ treatment can be improved greatly. Several Polβ inhibitors that have been identified could not become approved drugs due to lack of potency or specificity. To find therapeutic candidates with exquisite specificity and high affinity to Polβ, phage display technology was used in the current research. We screened out a candidate Polβ inhibitor, 10 D, that can inhibit the activity of Polβand SP-BER (Short-Patch Base excision Repair) pathway. Co-treatment with 10 D enhanced the sensitivity of colorectal cancer (CRC) cells to TMZ both in vitro and in vivo. Our data suggested that the novel Polβ inhibitor we identified can improve TMZ efficacy and optimize CRC chemotherapy.

Keywords:

• Inhibitor
• Polβ
• CRC
• DNA repair
• TMZ

Disclosure statement

There are no potential conflicts of interest to disclose.

Additional information

Funding

This work was supported by the Ministry of Education, Science, and Technology of China [2013CB911600,NCET-13-0868] the Jiangsu Provincial Natural Science Foundation (BK20141448), CJ20160051, the Research Fund for the Doctoral Program of Higher Education of China (RFDP) (20133207110005), the Priority Academic Program Development of Jiangsu Higher Education Institutions (20110101), and the Project Sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (2015104SBJ0090).