A novel 14-deoxy-12-hydroxyandrographolide analogue promotes apoptosis in colorectal cancer through ROS-dependent endoplasmic reticulum stress activation
Issued Date
2026-12-01
Resource Type
eISSN
27306011
Scopus ID
2-s2.0-105040660832
Journal Title
Discover Oncology
Volume
17
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Discover Oncology Vol.17 No.1 (2026)
Suggested Citation
Reabroi S., Kasemsuk T., Saeeng R., Chairoungdua A. A novel 14-deoxy-12-hydroxyandrographolide analogue promotes apoptosis in colorectal cancer through ROS-dependent endoplasmic reticulum stress activation. Discover Oncology Vol.17 No.1 (2026). doi:10.1007/s12672-026-05052-7 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/117168
Title
A novel 14-deoxy-12-hydroxyandrographolide analogue promotes apoptosis in colorectal cancer through ROS-dependent endoplasmic reticulum stress activation
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Author's Affiliation
Corresponding Author(s)
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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.