In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

Xin Ya  Xu; Siu Wai  Tsang; Yi Fu  Guan; Kang Lun  Liu; Wen Hui  Pan; Chu Shing  Lam; Kwan Ming  Lee; Yi Xuan  Xia; Wen Jian  Xie; Wing Yan Wong; Magnolia Muk Lan Lee; William Chi Shing Tai; Hong Jie  Zhang

doi:10.1021/acs.jmedchem.8b01742

In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

Xin Ya Xu, Siu Wai Tsang, Yi Fu Guan, Kang Lun Liu, Wen Hui Pan, Chu Shing Lam, Kwan Ming Lee, Yi Xuan Xia, Wen Jian Xie, Wing Yan Wong, Magnolia Muk Lan Lee, William Chi Shing Tai, Hong Jie Zhang^*

^*Corresponding author for this work

Chinese Medicine - Teaching and Research Division

Research output: Contribution to journal › Journal article › peer-review

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Abstract

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI₅₀ 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

Original language	English
Pages (from-to)	1541–1561
Number of pages	21
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	3
Early online date	11 Jan 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01742
Publication status	Published - 14 Feb 2019

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Molecular Medicine
Drug Discovery

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Xu, X. Y., Tsang, S. W., Guan, Y. F., Liu, K. L., Pan, W. H., Lam, C. S., Lee, K. M., Xia, Y. X., Xie, W. J., Wong, W. Y., Lee, M. M. L., Tai, W. C. S., & Zhang, H. J. (2019). In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence. Journal of Medicinal Chemistry, 62(3), 1541–1561. https://doi.org/10.1021/acs.jmedchem.8b01742

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title = "In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence",

abstract = "Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.",

author = "Xu, {Xin Ya} and Tsang, {Siu Wai} and Guan, {Yi Fu} and Liu, {Kang Lun} and Pan, {Wen Hui} and Lam, {Chu Shing} and Lee, {Kwan Ming} and Xia, {Yi Xuan} and Xie, {Wen Jian} and Wong, {Wing Yan} and Lee, {Magnolia Muk Lan} and Tai, {William Chi Shing} and Zhang, {Hong Jie}",

note = "Funding information: This project was supported by the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKBU 12103014), the Hong Kong Baptist University (HKBU) Interdisciplinary Research Matching Scheme (RC-IRMS/12-13/03, RC-IRMS/15-16/02, and RC-IRMS/16-17/02), the Hong Kong Baptist University (HKBU) Matching Proof-of-Concept Fund (MPCF) (MPCF-003-2017/18), the Innovation and Technology Fund of Hong Kong Special Administrative Region, China (Project No. ITS/131/12) and Faculty Research Grant, Hong Kong Baptist University (FRG1/13-14/029). The authors thank Francis Lee for conducting and William Rose and Robert Wild for arranging and overseeing the assessment of miliusol (1) and miliusate (2) against the cancer-resistant cells at Bristol-Myers Squibb, NJ. They acknowledge The National Cancer Institute (NCI), MD, for bioactivity evaluation of miliusol (1), miliusate (2), and miliusane I (3) in the NCI-60 cell lines. Publisher copyright: {\textcopyright} 2019 American Chemical Society",

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doi = "10.1021/acs.jmedchem.8b01742",

language = "English",

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T1 - In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

AU - Xu, Xin Ya

AU - Tsang, Siu Wai

AU - Guan, Yi Fu

AU - Liu, Kang Lun

AU - Pan, Wen Hui

AU - Lam, Chu Shing

AU - Lee, Kwan Ming

AU - Xia, Yi Xuan

AU - Xie, Wen Jian

AU - Wong, Wing Yan

AU - Lee, Magnolia Muk Lan

AU - Tai, William Chi Shing

AU - Zhang, Hong Jie

N1 - Funding information: This project was supported by the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKBU 12103014), the Hong Kong Baptist University (HKBU) Interdisciplinary Research Matching Scheme (RC-IRMS/12-13/03, RC-IRMS/15-16/02, and RC-IRMS/16-17/02), the Hong Kong Baptist University (HKBU) Matching Proof-of-Concept Fund (MPCF) (MPCF-003-2017/18), the Innovation and Technology Fund of Hong Kong Special Administrative Region, China (Project No. ITS/131/12) and Faculty Research Grant, Hong Kong Baptist University (FRG1/13-14/029). The authors thank Francis Lee for conducting and William Rose and Robert Wild for arranging and overseeing the assessment of miliusol (1) and miliusate (2) against the cancer-resistant cells at Bristol-Myers Squibb, NJ. They acknowledge The National Cancer Institute (NCI), MD, for bioactivity evaluation of miliusol (1), miliusate (2), and miliusane I (3) in the NCI-60 cell lines. Publisher copyright: © 2019 American Chemical Society

PY - 2019/2/14

Y1 - 2019/2/14

N2 - Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

AB - Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

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SN - 0022-2623

VL - 62

SP - 1541

EP - 1561

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -

In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

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