Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer

Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. To elucidate the therapeutic effect and underlyi...

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Bibliographic Details
Published in:	Journal of ethnopharmacology Vol. 336; p. 118754
Main Authors:	Wu, Tao, Yu, Yun, Tu, Xinyue, Ye, Lihua, Wang, Jiaying, Xie, Chenjun, Kuang, Keke, Yu, Ying, Zhuge, Weishan, Wang, Zhonglin, Cui, Ri, Zheng, Yihu
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 10-01-2025
Subjects:	Animals Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Cell Line, Tumor Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Drug Synergism Endoplasmic Reticulum Stress - drug effects ER stress HCT116 Cells HSPD1 Humans Male MAP Kinase Signaling System - drug effects Mice Mice, Inbred BALB C Mice, Nude Oxaliplatin Oxaliplatin - pharmacology Reactive Oxygen Species - metabolism ROS Saponins - pharmacology Triterpenes - pharmacology Tubeimoside-I Xenograft Model Antitumor Assays NAT JNK Colorectal cancer ER stress siRNA PERK ER HSPD1 HSPs DCFH-DA NAC Oxaliplatin Tubeimoside-I CRC NC UPR ROS OXA ATF4
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Summary:	Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients. [Display omitted] •The combination of TBM and oxaliplatin exerted synergistic anti-CRC activity both in vitro and in vivo.•Combination treatment with TBM and oxaliplatin triggered ROS-mediated ER stress, JNK and p38 MAPK signaling pathways.•TBM is a potent HSPD1 inhibitor.•Silencing HSPD1 potentiated anti-CRC activities of TBM by stimulating ER stress and MAPK signaling pathways.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0378-8741 1872-7573 1872-7573
DOI:	10.1016/j.jep.2024.118754