ABT-888 and quinacrine induced apoptosis in metastatic breast cancer stem cells by inhibiting base excision repair via adenomatous polyposis coli |
| |
| Affiliation: | 1. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;2. Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA;3. Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, USA;1. Plastic and Aesthetic surgery Center, The First Affiliated Hospital of Harbin Medical University, No.143 Yiman Road, Nangang District, Harbin, PR China;2. Department of Oncological Surgery, Heilongjiang Provincial Hospital, No.82 Zhongshan Road, Xiangfang District, Harbin, PR China;1. Department of Oncology, Shaanxi Provincial People''s Hospital, Xi''an 710068, Shaanxi, China;2. Fujian Key Laboratory of Aptamer Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, China;3. Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School, Fuzhou 350108, Fujian, China;4. the 900th Hospital, Fujian Medical University, Fuzhou 350108, Fujian, China;5. Department of Pathology, Shaanxi Provincial People''s Hospital, Xi''an 710068, Shaanxi, China;6. Xi''an Medical University, Xi''an 710021, Shaanxi, China;7. Department of Dermatology, Shaanxi Provincial People''s Hospital, Xi''an 710068, Shaanxi, China;8. Department of Emergency, Shaanxi Provincial People''s Hospital, Xi''an 710068, Shaanxi, China;9. Center for Reproductive Medicine, Naval Medical Center, Second, Military Medical University, Shanghai 200052, China;1. Department of Surgery, Houston Methodist Hospital, 6550 Fannin St., Smith Tower 1661, Houston, TX 77030, United States;2. Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, United States;3. Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main St., OPC 24, Houston, TX 77030, United States;4. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza Mail Stop BCM225, Houston, TX 77030, United States |
| |
| Abstract: | PARP inhibitors in combination with other agents are in clinical trial against cancer, but its effect on cancer stem cells (CSCs) is limited. CSCs are responsible for drug resistance, metastasis and cancer relapse due to high DNA repair capacity. Here, we present preclinical effects of Quinacrine (QC) with ABT-888, a PARP inhibitor, on highly metastatic breast cancer stem cells (mBCSCs). An increased level of Adenomatous polyposis coli (APC) was noted after treatment with ABT-888 in QC pre-treated mBCSCs cells. Increased APC physically interacts with PARP-1 and inhibits PARylation causing the non assembly of base excision repair (BER) multiprotein complex, resulting in an irreparable DNA damage and subsequent apoptosis. Knockdown of APC in mBCSCs inhibited DNA damage, increased BER and PARylation, reduces apoptosis while the over-expression of APC in BT20 (APC low expressing) cells reversed the effect. Thus, combination of QC and ABT-888 decreased mBCSCs growth by activating APC and inhibiting BER within the cells. |
| |
| Keywords: | Cancer stem cells PARP inhibitor ABT-888 Quinacrine APC |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
