Ling-Wei Hii1,2, Felicia Fei-Lei Chung3, Jaslyn Sian-Siu Soo4, Boon Shing Tan5, Chun-Wai Mai6,7, Chee-Onn Leong8,9. 1. Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. 2. School of Postgraduate Studies and Research, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. 3. Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France. 4. Cancer Research Malaysia, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia. 5. Institute of Biological Chemistry, Academia Sinica, 128, Academia Road Sec. 2, Nankang, Taipei, 115, Taiwan. 6. Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. 7. Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. 8. Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. cheeonn_leong@imu.edu.my. 9. Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. cheeonn_leong@imu.edu.my.
Abstract
PURPOSE: Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis. METHODS: By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs. RESULTS: We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype. CONCLUSION: In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.
PURPOSE:Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis. METHODS: By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs. RESULTS: We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype. CONCLUSION: In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.
Entities:
Keywords:
Breast cancer; Cancer stem cells; Doxorubicin; Drug combination; HDAC inhibitors; Quisinostat
Authors: Leila Mirsadeghi; Reza Haji Hosseini; Ali Mohammad Banaei-Moghaddam; Kaveh Kavousi Journal: BMC Med Genomics Date: 2021-05-07 Impact factor: 3.063
Authors: Feng Chi; Jiayi Liu; Samuel W Brady; Patrick A Cosgrove; Aritro Nath; Jasmine A McQuerry; Sumana Majumdar; Philip J Moos; Jeffrey T Chang; Michael Kahn; Andrea H Bild Journal: Transl Oncol Date: 2020-11-19 Impact factor: 4.243