Abstract
Oblongifolin C (OC) and guttiferone K (GUTK) are two anticancer compounds extracted from Garcinia yunnanensis Hu, but they act by different mechanisms. In this study we investigated whether a combination of OC and GUTK (1:1 molar ratio) could produce synergistic anticancer effects against human colorectal cancer cells in vitro. For comparison, we also examined the anticancer efficacy of ethanol extracts from G yunnanensis fruit, which contain OC and GUTK up to 5%. Compared to OC and GUTK alone, the combination of OC and GUTK as well as the ethanol extracts more potently inhibited the cancer cell growth with IC50 values of 3.4 μmol/L and 3.85 μg/mL, respectively. Furthermore, OC and GUTK displayed synergistic inhibition on HCT116 cells: co-treatment with OC and GUTK induced more prominent apoptosis than treatment with either drug alone. Moreover, the combination of OC and GUTK markedly increased cleavage of casapse-3 and PARP, and enhanced cellular ROS production and increased JNK protein phosphorylation. In addition, the combination of OC and GUTK exerted stronger effects under nutrient-deprived conditions than in complete medium, suggesting that autophagy played an essential role in regulating OC- and GUTK-mediated cell death. OC and GUTK are the main components that contribute to the anticancer activity of G yunnanensis and the compounds have apoptosis-inducing effects in HCT116 cells in vitro.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86.
DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64: 252–71.
Liu EY, Ryan KM . Autophagy and cancer — issues we need to digest. J Cell Sci 2012; 125: 2349–58.
Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012; 45: 487–98.
Farooqi AA, Fayyaz S, Hou MF, Li KT, Tang JY, Chang HW . Reactive oxygen species and autophagy modulation in non-marine drugs and marine drugs. Mar Drugs 2014; 12: 5408–24.
Filomeni G, De Zio D, Cecconi F . Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ 2015; 22: 377–88.
Kim GT, Lee SH, Kim JI, Kim YM . Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. Int J Mol Med 2014; 33: 863–9.
Guo X, Chen S, Zhang Z, Dobrovolsky VN, Dial SL, Guo L, et al. Reactive oxygen species and c-Jun N-terminal kinases contribute to TEMPO-induced apoptosis in L5178Y cells. Chem Biol Interact 2015; 235: 27–36.
Romano B, Borrelli F, Pagano E, Cascio MG, Pertwee RG, Izzo AA . Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine 2014; 21: 631–9.
Goldar S, Khaniani MS, Derakhshan SM, Baradaran B . Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac J Cancer Prev 2015; 16: 2129–44.
Ovadje P, Roma A, Steckle M, Nicoletti L, Arnason JT, Pandey S . Advances in the research and development of natural health products as main stream cancer therapeutics. Evid Based Complement Alternat Med 2015; 2015: 751348. doi: 10.1155/2015/751348.
Wu SB, Long C, Kennelly EJ . Structural diversity and bioactivities of natural benzophenones. Nat Prod Rep 2014; 31: 1158–74.
Anholeti MC, Paiva SR, Figueiredo MR, Kaplan MA . Chemosystematic aspects of polyisoprenylated benzophenones from the genus Clusia. An Acad Bras Cienc 2015; 87: 289–301.
Xu G, Feng C, Zhou Y, Han QB, Qiao CF, Huang SX, et al. Bioassay and ultraperformance liquid chromatography/mass spectrometry guided isolation of apoptosis-inducing benzophenones and xanthone from the pericarp of Garcinia yunnanensis Hu. J Agric Food Chem 2008; 56: 11144–50.
Feng C, Zhou LY, Yu T, Xu G, Tian HL, Xu JJ, et al. A new anticancer compound, oblongifolin C, inhibits tumor growth and promotes apoptosis in HeLa cells through Bax activation. Int J Cancer 2012; 131: 1445–54.
Lao Y, Wan G, Liu Z, Wang X, Ruan P, Xu W, et al. The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation. Autophagy 2014; 10: 736–49.
Wang X, Lao Y, Xu N, Xi Z, Wu M, Wang H, et al. Oblongifolin C inhibits metastasis by up-regulating keratin 18 and tubulins. Sci Rep 2015; 5: 10293.
Wu M, Lao Y, Xu N, Wang X, Tan H, Fu W, et al. Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death. Phytomedicine 2015; 22: 902–10.
Kan WL, Yin C, Xu HX, Xu G, To KK, Cho CH, et al. Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G0/G1 cell cycle arrest and apoptosis. Int J Cancer 2013; 132: 707–16.
Chou TC . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58: 621–81.
Chou TC . Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010; 70: 440–6.
van Beek TA, Montoro P . Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A 2009; 1216: 2002–32.
Nash KM, Shah ZA . Current perspectives on the beneficial role of Ginkgo biloba in neurological and cerebrovascular disorders. Integr Med Insights 2015; 10: 1–9.
Date AA, Destache CJ . Natural polyphenols: potential in the prevention of sexually transmitted viral infections. Drug Discov Today 2016; 21: 333–41.
U.S Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: Botanical Drug Products 2004.
Wu ZY, Chen J . Flora of Yunnan. Beijing: Science Press; 1991.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81173485 and 81273403) and the Natural Science Foundation of Shanghai (No 14ZR1441300).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Supplementary information is available on the Acta Pharmacologica Sinica's web site.
Supplementary information
Supplementary Figure S1
Among the fractions, GYFB (OC+GUTK fraction) potently inhibited HCT116 cells in a dose-dependent manner, where as GYFA (NO OC+GUTK fraction) exerted almost no effect on cell viability using a SYBR green assay. (JPG 402 kb)
Supplementary Figure S2
OC, GUTK and their combination (1:1 molar ratio) significantly decreased the viability of HCT116 cells in a dose-dependent manner according to LDH assays. (JPG 100 kb)
Supplementary Figure S3
Pretreatment with SP600125 or NAC for 0.5 h did not decrease the percentage of sub-G1 cells induced by the OC and GUTK combination treatment. (JPG 603 kb)
Rights and permissions
About this article
Cite this article
Li, H., Meng, Xx., Zhang, L. et al. Oblongifolin C and guttiferone K extracted from Garcinia yunnanensis fruit synergistically induce apoptosis in human colorectal cancer cells in vitro. Acta Pharmacol Sin 38, 252–263 (2017). https://doi.org/10.1038/aps.2016.101
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2016.101
Keywords
This article is cited by
-
Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols
Natural Products and Bioprospecting (2021)
