A novel 14-deoxy-12-hydroxyandrographolide analogue promotes apoptosis in colorectal cancer through ROS-dependent endoplasmic reticulum stress activation.

Authors

Somrudee Reabroi, Teerapich Kasemsuk, Rungnapha Saeeng, Arthit Chairoungdua

Published in

Discover oncology. Volume 17. Issue 1. Apr 20, 2026. Epub Apr 20, 2026.

Abstract

Colorectal cancer is the second leading cause of cancer-related mortality worldwide, highlighting the critical need for novel therapeutic strategies. In this study, we investigated the anticancer activity and molecular mechanisms of RS-PP-059, a derivative of 14-deoxy-12-hydroxyandrographolide, in colorectal cancer cells. RS-PP-059 exhibited potent cytotoxicity and selectivity toward HT-29 cells, suppressing viability and clonogenic growth. The compound induced apoptotic cell death, as shown by increased Annexin V-positive cells, PARP-1 cleavage, p53 activation, and γ-H2AX accumulation, indicating DNA damage, and was accompanied by a reduction in total caspase-3 protein levels. Mechanistically, RS-PP-059 triggered endoplasmic reticulum (ER) stress and unfolded protein response (UPR), upregulating key markers including GRP78, IRE1α, CHOP, and spliced XBP1 (XBP1s) at both mRNA and protein levels. Co-treatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA) only partially reversed these effects, suggesting robust ER stress activation by RS-PP-059. In parallel, RS-PP-059 increased intracellular reactive oxygen species (ROS) in a time-dependent manner, accompanied by differential regulation of antioxidant genes with strong induction of HO-1 and suppression of CAT, SOD1, and GPX-1. Importantly, pretreatment with N-acetyl-L-cysteine (NAC) abolished ROS accumulation, ER stress activation, apoptosis, and loss of viability, confirming the ROS-dependent mechanism. In conclusion, our findings demonstrate that RS-PP-059 exerts potent anticancer effects in colorectal cancer cells by promoting ROS-mediated ER stress, leading to DNA damage and apoptosis.
The online version contains supplementary material available at 10.1007/s12672-026-05052-7.

PMID:
42008072
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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