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Bioactive Constituents, Metabolites, and Functions
Alkaloids from Piper nigrum synergistically enhanced the effect of paclitaxel against paclitaxel-resistant cervical cancer cells through the downregulation of Mcl-1 Zhoufan Xie, Yulu Wei, Jie Xu, Jiachuan Lei, and Jianqing Yu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b01320 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 22, 2019
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Journal of Agricultural and Food Chemistry
Alkaloids from Piper nigrum synergistically enhanced the effect of paclitaxel against paclitaxel-resistant cervical cancer cells through the downregulation of Mcl-1 Zhoufan Xie,†,§ Yulu Wei,†,§ Jie Xu,† Jiachuan Lei,‡ Jianqing Yu,*,† †Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan
University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences,Wuhan 430071, China. ‡
Renmin Hospital, Wuhan University, Wuhan 430060, China.
*Correspondence:
Jianqing Yu
Tel.: +86-27-68759983; fax: +86-27-87669560. E-mail address:
[email protected]. Full postal address：School of Pharmaceutical Sciences, Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, China.
§
Zhoufan Xie and Yulu Wei contributed equally to this work.
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Journal of Agricultural and Food Chemistry
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ABSTRACT
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In the current study, nine amide alkaloids, including two new dimeric amides and a
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new natural product, were identified from Piper nigrum. Among them, seven
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compounds sensitized paclitaxel-resistant cervical cancer cells HeLa/PTX to
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paclitaxel. Piperine was a major component obtained from Piper nigrum, and its
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sensitization mechanism was investigated. Combination treatment enhanced cell
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apoptosis which was mediated by downregulation of phospho-Akt and Mcl-1.
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Piperine (50 μM) combined with paclitaxel (200 nM) downregulated Mcl-1 protein
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expression with a decrease of 35.9 ± 9.5% (P < 0.05). Moreover, overexpression of
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Mcl-1 attenuated the inhibitory effect of this combination. Furthermore, combination
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treatments of six dimeric amide alkaloids and paclitaxel all downregulated Mcl-1
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protein expression with the decrease ranged from 23.5 ± 9.7% to 41.7 ± 7.2% (P
