Combinatorial Implications of Nrf2 Inhibitors with FN3K Inhibitor: In vitro Breast Cancer Study

Author:

Beeraka Narasimha M.123,Zhang Jin4,Zhao Di5,Liu Junqi16,A U Chinnappa7,Vikram PR Hemanth38,Shivaprakash Priyanka9,Bannimath Namitha10,Manogaran Prasath11,Sinelnikov Mikhail Y.212,Bannimath Gurupadayya3,Fan Ruitai16

Affiliation:

1. Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Str., Zhengzhou 450052, China

2. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia

3. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India

4. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA

5. Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

6. Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Str., Zhengzhou 450052, China

7. Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India

8. Xenone Healthcare Pvt. Ltd, #318, Third Floor, US Complex, Jasola, New Delhi 110076, India

9. Faculty of Life Sciences, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India

10. Department of Pharmacology and Toxicology, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India

11. Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu 641046, India

12. Sinelab Biomedical Research Center, Minnesota 55905, USA

Abstract

Background:: Platinum derivatives are chemotherapeutic agents preferred for the treatment of cancers including breast cancer. Oxaliplatin is an anticancer drug that is in phase II studies to treat metastatic breast cancer. However, its usage is constrained by chemoresistance and dose-related side effects. Objective:: The objective of this study is to examine the combinatorial efficacy of brusatol, an Nrf2 blocker, with oxaliplatin (a proven FN3K blocker in our study) in mitigating breast cancer growth in vitro. Methods:: We performed cytotoxicity assays, combination index (CI) analysis, colony formation assays, apoptosis assays, and Western blotting. Results:: Results of our study described the chemosensitizing efficacy of brusatol in combination with lowdose oxaliplatin against breast cancer through synergistic effects in both BT-474 and T47D cells. A significant mitigation in the migration rate of these cancer cells was observed with the combination regimen, which is equivalent to the IC-50 dose of oxaliplatin (125 μM). Furthermore, ROS-mediated and apoptotic modes of cell death were observed with a combinatorial regimen. Colony formation of breast cancer cell lines was mitigated with a combinatorial regimen of bursatol and oxaliplatin than the individual treatment regimen. FN3K expression downregulated with oxaliplatin in T47D cells. The mitigation of FN3K protein expression with a combination regimen was not observed but the Nrf2 downstream antioxidant signaling proteins were significantly downregulated with a combination regimen similar to individual drug regimens. Conclusion:: Our study concluded the combination efficacy of phytochemicals like brusatol in combination with low-dose oxaliplatin (FN3K blocker), which could enhance the chemosensitizing effect in breast cancer and minimize the overall dose requirement of oxaliplatin.

Funder

National Natural Science Foundation of China

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmacology

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