A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and...
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/5/2892 |
| _version_ | 1797474781801480192 |
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| author | Chenchen Tian Yufan Wei Jianjun Li Zhi Huang Qiong Wang Yingxue Lin Xingping Lv Yanan Chen Yan Fan Peiqing Sun Rong Xiang Antao Chang Shuang Yang |
| author_facet | Chenchen Tian Yufan Wei Jianjun Li Zhi Huang Qiong Wang Yingxue Lin Xingping Lv Yanan Chen Yan Fan Peiqing Sun Rong Xiang Antao Chang Shuang Yang |
| author_sort | Chenchen Tian |
| collection | DOAJ |
| description | In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency. |
| first_indexed | 2024-03-09T20:35:57Z |
| format | Article |
| id | doaj.art-69b68b05a7be489b8313ba058a890afe |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:35:57Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-69b68b05a7be489b8313ba058a890afe2023-11-23T23:11:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01235289210.3390/ijms23052892A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian CancerChenchen Tian0Yufan Wei1Jianjun Li2Zhi Huang3Qiong Wang4Yingxue Lin5Xingping Lv6Yanan Chen7Yan Fan8Peiqing Sun9Rong Xiang10Antao Chang11Shuang Yang12Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaDepartment of Cancer Biology, Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC 27157, USATianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaDepartment of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, ChinaTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, ChinaIn recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.https://www.mdpi.com/1422-0067/23/5/2892breast cancerovarian cancerZC-22PARP inhibitorCDK4/6 inhibitor |
| spellingShingle | Chenchen Tian Yufan Wei Jianjun Li Zhi Huang Qiong Wang Yingxue Lin Xingping Lv Yanan Chen Yan Fan Peiqing Sun Rong Xiang Antao Chang Shuang Yang A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer International Journal of Molecular Sciences breast cancer ovarian cancer ZC-22 PARP inhibitor CDK4/6 inhibitor |
| title | A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer |
| title_full | A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer |
| title_fullStr | A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer |
| title_full_unstemmed | A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer |
| title_short | A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer |
| title_sort | novel cdk4 6 and parp dual inhibitor zc 22 effectively suppresses tumor growth and improves the response to cisplatin treatment in breast and ovarian cancer |
| topic | breast cancer ovarian cancer ZC-22 PARP inhibitor CDK4/6 inhibitor |
| url | https://www.mdpi.com/1422-0067/23/5/2892 |
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