Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment
Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical mo...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153868 |
| _version_ | 1828823734455107584 |
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| author | Sydney Stern Dongdong Liang Linhao Li Ritika Kurian Caitlin Lynch Srilatha Sakamuru Scott Heyward Junran Zhang Kafayat Ajoke Kareem Young Wook Chun Ruili Huang Menghang Xia Charles C. Hong Fengtian Xue Hongbing Wang |
| author_facet | Sydney Stern Dongdong Liang Linhao Li Ritika Kurian Caitlin Lynch Srilatha Sakamuru Scott Heyward Junran Zhang Kafayat Ajoke Kareem Young Wook Chun Ruili Huang Menghang Xia Charles C. Hong Fengtian Xue Hongbing Wang |
| author_sort | Sydney Stern |
| collection | DOAJ |
| description | Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular coculture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Furthermore, CN06 preserves the viability and function of human iPSC–derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as potentially novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy/toxicity ratio of CPA/DOX-containing chemotherapy. |
| first_indexed | 2024-12-12T13:40:56Z |
| format | Article |
| id | doaj.art-1a8ce16626d14dd984fe688ea0acc24d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:40:56Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-1a8ce16626d14dd984fe688ea0acc24d2022-12-22T00:22:48ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-06-01712Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatmentSydney SternDongdong LiangLinhao LiRitika KurianCaitlin LynchSrilatha SakamuruScott HeywardJunran ZhangKafayat Ajoke KareemYoung Wook ChunRuili HuangMenghang XiaCharles C. HongFengtian XueHongbing WangCyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular coculture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Furthermore, CN06 preserves the viability and function of human iPSC–derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as potentially novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy/toxicity ratio of CPA/DOX-containing chemotherapy.https://doi.org/10.1172/jci.insight.153868OncologyTherapeutics |
| spellingShingle | Sydney Stern Dongdong Liang Linhao Li Ritika Kurian Caitlin Lynch Srilatha Sakamuru Scott Heyward Junran Zhang Kafayat Ajoke Kareem Young Wook Chun Ruili Huang Menghang Xia Charles C. Hong Fengtian Xue Hongbing Wang Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment JCI Insight Oncology Therapeutics |
| title | Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment |
| title_full | Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment |
| title_fullStr | Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment |
| title_full_unstemmed | Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment |
| title_short | Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment |
| title_sort | targeting car and nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin induced cardiotoxicity in triple negative breast cancer treatment |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.153868 |
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