Walailak Frontier 06, November 2018
Cancer drug discovery ‒ Targeting autophagy as a strategy for anti-cancer therapies
Natural product-based therapeutic agent for cancer
Autophagy, the major self-degradation process, has a fundamental role in the maintenance of cellular homeostasis of normal cells. Autophagy is responsible for the elimination of damaged cellular components through the degradative organelle (also called autophagolysosome) and recycling of cellular materials to maintain energy balance and cellular protein homeostasis. In the case of cancer, autophagy plays dual roles by both inhibiting and promoting cancer cell death. The cell death role of autophagy occurs when autophagy is excessively stimulated by various anti-cancer agents; thus, cytotoxic autophagy induction may be beneficial for treating cancer. Asst.Prof.Dr.Warangkana Chunglok and her research collaborators works in the field of anti-cancer drug discovery and specifically with multidrug-resistant cancer.
Our laboratory has successfully characterized two distinct phenotypes of oral squamous cell carcinoma cells with epithelial (CLS-354/WT) and mesenchymal-like (CLS-354/DX) phenotypes. CLS-354/DX cells had higher invasive activity and were more resistant to standard chemotherapeutic drugs (cisplatin and camptothecin) than the parental CLS-354/WT cells. This aggressive cell line developed a multidrug-resistant phenotype via increasing the expression and activity of multidrug resistance-associated protein 1 (MRP1) transporters. This cell line has been used as a screening platform for the identification of novel anti-cancer drug candidates. For natural compound screening the isomahanine, carbazole alkaloid from Murraya koenigii leaves is capable of inducing cancer cell death, regardless of resistance, through the induction of cytotoxic autophagy (increase of GFP-LC3 puncta formation). Thus targeting autophagy via cytotoxic induction is a strategy for effectively overcoming multidrug-resistant cancer.
Utaipan T, Athipornchai A, Suksamrarn A, Chunsrivirot S, Chunglok W (2017). Isomahanine induces endoplasmic reticulum stress and simultaneously triggers p38 MAPK-mediated apoptosis and autophagy in multidrug-resistant human oral squamous cell carcinoma cells. Oncol Rep; 37: 1243-1252
Utaipan T, Athipornchai A, Suksamrarn A, Jirachotikoon C, Yuan X, Lertcanawanichakul M, Chunglok W (2017). Carbazole alkaloids from Murraya koenigii trigger apoptosis and autophagic flux inhibition in human oral squamous cell carcinoma cells. J Nat Med; 71: 158-169
Utaipan T, Sattayakhom A, Prachongsai I, Charong N, Chunglok W (2018). Reduction of intracellular-reactive oxygen species and diminished mitogen-activated protein kinases (MAPKs) activation are associated with oral squamous cell carcinoma cell aggressiveness. Walailak J Sci & Tech; 15: 131-141