Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation

Longgao XIAO; Yueqin ZHAO; Xiao DING; Hui LIU; Guangyu ZHU; Yanxi LI; Huan YAN; Xin FANG; Yuhan ZHAO; Haiyang LIU

doi:10.1016/S1875-5364(24)60592-3

Chinese Journal of Natural Medicines ›› 2024, Vol. 22 ›› Issue (11) :1011 -1019. DOI: 10.1016/S1875-5364(24)60592-3

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research-article

Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation

Longgao XIAO ¹^,²^,^∆
, Yueqin ZHAO ¹^,²^,^∆
, Xiao DING ¹
, Hui LIU ¹
, Guangyu ZHU ¹^,²
, Yanxi LI ¹
, Huan YAN ¹
, Xin FANG ¹^,^*
, Yuhan ZHAO ¹^,^*
, Haiyang LIU ¹^,³^,^*

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Abstract

Three novel sesquiterpenoid heterodimers, designated as auckcostusolides A-C (1-3), were isolated from Aucklandia costus leaves. The structures of compounds 1-3 were elucidated through comprehensive spectroscopic analysis, with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism (ECD) calculations. Notably, compounds 1 and 2, despite sharing identical planar structures derived from two identical sesquiterpenoids, exhibited opposite configurations at C-11 and C-8′. This configurational difference can be attributed to distinct Diels−Alder cycloaddition processes between the sesquiterpenoid monomers. Additionally, the cytotoxic effects of compounds 1-3 were evaluated against colorectal cancer HCT116 cells, fibrosarcoma HT1080 cells, and hepatocellular carcinoma HepG2 cells. Compounds 1-3 induced cell death was characterized by endoplasmic reticulum (ER) swelling and cytoplasmic vacuolization, typical morphological changes associated with paraptosis. Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of reactive oxygen species (ROS), activation of ER stress, and stimulation of the MAPK signaling pathway.

Keywords

Aucklandia costus / Sesquiterpenoid heterodimers / Auckcostusolides A-C / Paraptosis / MAPK signaling pathway

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Longgao XIAO, Yueqin ZHAO, Xiao DING, Hui LIU, Guangyu ZHU, Yanxi LI, Huan YAN, Xin FANG, Yuhan ZHAO, Haiyang LIU. Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation. Chinese Journal of Natural Medicines, 2024, 22(11): 1011-1019 DOI:10.1016/S1875-5364(24)60592-3

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