β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

doi:10.1007/s13659-023-00422-y

Natural Products and Bioprospecting ›› 2024, Vol. 14 ›› Issue (1): 3-3.DOI: 10.1007/s13659-023-00422-y

• ORIGINAL ARTICLES • Previous Articles Next Articles

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li

Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China

Received:2023-10-30 Online:2024-02-19 Published:2024-02-24
Contact: Lingmei Kong,E-mail:konglingmei@ynu.edu.cn;Yan Li,E-mail:yan.li@ynu.edu.cn
Supported by:
We thank Dr Hongbo Qin (Yunnan Minzu University) for the synthetic support. This study was funded by the National Natural Science Foundation of China (No. 32260159, 82360725, 81960738), the Yunnan Fundamental Research Projects (202301AS070022), Yunnan University (start-up grant to Y.L. and L.K.), the Central Guidance on Local Science and Technology Development Fund of Yunnan Province (202207AB110002), National Key R&D Program of China (2019YFE0109200), the central government guides local science and technology development fund (202207AA110007), the Yunnan Young & Elite Talents Project (YNWR-QNBJ-2020-084), the Youth Innovation Promotion Association CAS (to L.K.).

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li

Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China

通讯作者: Lingmei Kong,E-mail:konglingmei@ynu.edu.cn;Yan Li,E-mail:yan.li@ynu.edu.cn
基金资助:
We thank Dr Hongbo Qin (Yunnan Minzu University) for the synthetic support. This study was funded by the National Natural Science Foundation of China (No. 32260159, 82360725, 81960738), the Yunnan Fundamental Research Projects (202301AS070022), Yunnan University (start-up grant to Y.L. and L.K.), the Central Guidance on Local Science and Technology Development Fund of Yunnan Province (202207AB110002), National Key R&D Program of China (2019YFE0109200), the central government guides local science and technology development fund (202207AA110007), the Yunnan Young & Elite Talents Project (YNWR-QNBJ-2020-084), the Youth Innovation Promotion Association CAS (to L.K.).

Abstract

Abstract: Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC₅₀ value of 4.28 μM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.

Key words: Colorectal cancer, PI3K, Z86, Proliferation, Cell cycle arrest

摘要： Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC₅₀ value of 4.28 μM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.

关键词: Colorectal cancer, PI3K, Z86, Proliferation, Cell cycle arrest

Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K[J]. Natural Products and Bioprospecting, 2024, 14(1): 3-3.

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β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

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