Meng-Han Wu, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan
Chieh-Ju Sung, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan
Fan-Lu Kung, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan
Jih-Hwa Guh, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan
Yu Su, Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Shi-Pai, Taipei 11221, Taiwan
Lih-Ching Hsu, School of Pharmacy, National Taiwan University, Taipei 10050, TaiwanFollow

Autophagy/mitophagy, Colorectal cancer stem cells, Dihydroartemisinin, GATA6, Glucose metabolism

Colorectal cancer (CRC) is one of the leading causes of cancer-related death globally and discovering novel therapeuticagents to treat the disease, and prevent cancer metastasis and recurrence is an urgent medical need. Cancer stem cells(CSCs) capable of self-renewal and differentiation are generally considered the cause of tumor metastasis, recurrenceand chemoresistance. Hence, targeting CSCs may be a promising strategy for the treatment of cancer. GATA6, a zincfinger transcription factor, contributes to tumorigenesis in CRC and is related to cancer stemness. GATA6-overexpressing stable clones OE4 and OE6 derived from HCT116 cells were previously established and exhibitedincreased stemness properties. In this study, we found that OE4 and OE6 cells displayed CSC-like properties, includinghigher expression levels of stemness-related proteins, increased sphere forming capacity and resistance to 5-fluorouracil.OE4 and OE6 cells also showed increased glucose uptake capacity, another hallmark of CSCs. Therefore, these two cellclones were employed as a CSC-like cell model to search for potential colorectal CSC-targeting drugs. Among severalcompounds tested, dihydroartemisinin (DHA), an antimalarial drug, exerted better anticancer activity toward OE4 andOE6 relative to the empty vector-transfected HCT116 cells. DHA also inhibited sphere formation and impaired glucosemetabolism. DHA induced G0/G1 arrest and apoptosis. Moreover, DHA also induced reactive oxygen species andmitochondrial membrane potential loss. Thus, DHA caused mitochondrial damage which was confirmed by Seahorsemitochondrial stress test. DHA also increased LC3B-II and PINK1 protein levels, indicative of autophagy/mitophagy. Inconclusion, repurposing DHA may be a potential strategy against colorectal CSCs and further validation using in vivo models is warranted.

Wu, Meng-Han; Sung, Chieh-Ju; Kung, Fan-Lu; Guh, Jih-Hwa; Su, Yu; and Hsu, Lih-Ching (2025) "Repurposing dihydroartemisinin as a novel anticancer agent against colorectal cancer stem cells," Journal of Food and Drug Analysis: Vol. 33 : Iss. 3 , Article 7.
Available at: https://doi.org/10.38212/2224-6614.3552

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