title: Antitumor Activity of Spicatoside A by Modulation of Autophagy and Apoptosis in Human Colorectal Cancer Cells.
abstract: The antitumor activity of spicatoside A (1), a steroidal saponin isolated from the tuber of Liriope platyphylla, and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. Compound 1 induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with 1 for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1 (LAMP 1), and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase (MAPK) signaling, and increasing p53 levels. However, a prolonged exposure to 1 resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide (PI)-positive cell population. Apoptosis induced by 1 was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly-ADP-ribose polymerase (PARP). Further study revealed that cleavage of beclin 1 by caspases plays a critical role in the 1-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of 1 in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of 1 as a novel candidate in the treatment of human colorectal cancer cells.
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Won Kyung
authors.initials: WK
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Pyee
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: Department of Food Science and Nutrition, Andong National University , Andong 760-749, Republic of Korea.
authors.forename: Kun Ho
authors.initials: KH
authors.lastname: Son
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Republic of Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms; D045325:HCT116 Cells; D006801:Humans; D019668:Liliaceae / Q000737:chemistry*; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012503:Saponins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C546003:5-(1-(glucopyranosyloxymethyl)ethenyl)-2-methyl-2-cyclohexen-1-one; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D012503:Saponins; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases