CHEMICAL INVESTIGATION AND ANTIPROLIFERATIVE STUDIES OF ISOLATED POLYISOPRENYLATED BENZOPHENONES FROM STEM-BARK OF Garcinia maingayi

Sangeetha  Arullappan; Wong Fai  Chu; Lim Chan  Kiang; Vivien Jong Yi  Mian; Sim Kooi  Mow

doi:10.18006/2021.9(Spl-1-GCSGD_2020).S71.S84

Authors

Sangeetha Arullappan Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Perak Campus, Bandar Barat, Jalan Universiti, 31900 Kampar, Perak, Malaysia.
Wong Fai Chu Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Perak Campus, Bandar Barat, Jalan Universiti, 31900 Kampar, Perak, Malaysia.
Lim Chan Kiang Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Perak Campus, Bandar Barat, Jalan Universiti, 31900 Kampar, Perak, Malaysia.
Vivien Jong Yi Mian Centre for Applied Sciences, Faculty of Applied Sciences, Universiti Teknologi MARA, Samarahan Campus 2, Jalan Meranek, 94300 Kota Samarahan, Sarawak, Malaysia.
Sim Kooi Mow Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Perak Campus, Bandar Barat, Jalan Universiti, 31900 Kampar, Perak, Malaysia.

DOI:

https://doi.org/10.18006/2021.9(Spl-1-GCSGD_2020).S71.S84

Keywords:

Garcinia maingayi, Polyisoprenylated Benzophenones, Apoptosis, Caspases, Flow Cytometry

Abstract

In the current study, sequential solvents extraction from the stem bark of Garcinia maingayi, a native plant to Malaysia has led to the isolation of four polyisoprenylated benzophenones: 30-epi-cambogin (GB 1), 14-deoxy-30-epi-cambogin (GB 2), guttiferone F (GB 3), and 14-deoxy-guttiferone F (GB 4). The structures were elucidated using IR, optical rotation, and NMR spectral data. The compounds were evaluated for antiproliferative effect using MTT assay, apoptosis using Annexin V/7-AAD flow cytometry, cell cycle progression, and activation of caspases 3/7, 8 and 9 and BCL2 mRNA expression in MCF-7, HeLa, and HepG2 cancer cell lines. Compounds GB 1 to GB 4 exhibited a remarkable antiproliferative effect on HeLa, MCF-7, and HepG2 cells with IC₅₀ values ranging from 5 to 45 µM. Compounds GB 1 to GB 4 induced significant cell cycle arrest in the G1 phase corroborated with the decrease in the number of MCF-7 and HepG2 cells in S and G2/M phases (P<0.05). Compounds GB 1 to GB 4 induced apoptosis at 48 h. Further, among these, compounds GB 1 and GB 2 induced significant levels of caspases 3 and 9 in HeLa cells, while GB 3 induced caspase 9 activities in both MCF-7 and HepG2 cells. No significant induction of caspase 8 was observed suggesting that the apoptotic effects are mainly mediated through the intrinsic pathway. Only compound GB 1 inhibited the BCL2 mRNA expression significantly in all treated cancer cells. In conclusion, these compounds possess anticancer properties and thus further investigation is crucial on the mechanistic study, structure-activity relationship, and identification of putative molecular targets.

References

Ahmad A, Sarkar SH, Aboukameel A, Ali S, Biersack B, Seibt S, Li Y, Bao B, Kong D, Banerjee S, Schobert R, Padhye SB, Sarkar FH (2012) Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signalling. Carcinogenesis 33(12): 2450-2456. doi: 10.1093/carcin/bgs290.

BD Biosciences (2008) Technical data sheet: PE annexin V apoptosis detection kit[Online]. Available at: http://www.bdbiosciences.com/ds/pm/tds/559763.pdf Accessed: 17 December 2018.

Bradshaw TD, Matthews CS, Cookson J, Chew EH, Shah M, Bailey K, Monks A, Harris E, Westwell AD, Wells G, Laughton CA, Stevens MFG (2005) Elucidation of thioredoxin as a molecular target for antitumor quinols. Cancer Research 65(9): 3911-3919.

Chai PK (2000) A check-list of flora, fauna, food and medicinal plants, Yokohama-City, Japan: International Tropical Timber Organization and Sarawak, Malaysia, Sarawak Forest Department.

Cheng GLE, Cheow YL (2008) Secondary metabolites from two Garcinia species and their biological activities. Chemistry: An Asian Journal 20(1): 343-351.

Crompton M (2000) Bax, Bid and the permeabilization of the mitochondrial outer membrane in apoptosis. Journal of Biological Chemistry 280(46): 38271-38275.

Domagoj V, Wayne JF (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clinical Cancer Research 13(20): 5995-6000.

Ferlay JI, Soerjomataram R, Dikshit S, Eser C, Mathers M, Rebelo DM et al. (2015) Cancer incidence and mortality worldwide: Sources, methods and major patterns in Globocan 2012. International Journal of Cancer 136(5): 359-386.

Freshney RI (2005) Culture of animal cells: A manual of basic techniques (5th Eds), John Wiley & Sons, Inc., New Jersey. Fuller RW, Blunt JW, Boswell JL, Cardellina JH, Boyd MR (1999) Guttiferone F, the first prenylated benzophenone from Allanblackia stuhlmannii. Journal of Natural Products 62(1):130-132.

Hemshekhar M, Sunitha K, Santhosh MS, Devaraja S, Kemparaju K, Vishwanath BS, Niranjana SR, et al (2011) An overview on genus Garcinia: Phytochemical and therapeutic aspects. Phytochemical Review 10: 325-351.

Jabit ML, Wahyuni FS, Khalid R, Israf DA, Shaari K, Lajis NH, et al. (2009) Cytotoxic and nitric oxide inhibitory activities of methanol extracts of Garcinia species. Pharmaceutical Biology 47(11): 1019-1026.

Jin S, Shi K, Liu L, Chen Y, Yang G (2019) Xanthones from the bark of Garcinia xanthochymus and the mechanism of induced apoptosis in human hepatocellular carcinoma HepG2 cells via the mitochondrial pathway. International Journal of Molecular Sciences 20(19): 4803.

Joseph GS, Jayaprakasha GK, Selvi AT, Jena BS, Sakariah KK (2005) Antiflatoxigenic and antioxidant activities of Garcinia extracts. International Journal of Food Microbiology 101: 153-160.

Kai-Wei L, A-Mei H, Shyh-Chyun Y, Jing-Ru W, Tzyh-Chyuan H, Yeong-Shiau P, Chun-Nan L (2012) Cytotoxic and antioxidant constituents from Garcinia subelliptica. Food Chemistry135: 851-859.

Kenji M, Akao Y, Kobayashi E, Ito T, Ohguchi K, Tanaka T, Iinuma M, Nozawa Y (2003) Cytotoxic benzophenone derivatives from Garcinia species displays a strong apoptosis-inducing effect against human leukaemia cell lines. Biological and Pharmaceutical Bulletin 26(4):569-571.

Kleinsmith LJ (2006) Principles of cancer biology. San Francisco, Pearson International Edition.

Kochummen KM (1998) Garcinia maingayi [Online]. Available at: http://www.iucnredlist.org/details/37830/0 [Accessed: 14 January 2016].

Krishnamoorthy V, Nagappan P,Sereen AK, Rajendran R (2014) Preliminary phytochemical screening of the fruit rind of Garcinia cambogia and leaves of Bauhinia variegate: A comparative study. International Journal of Current Microbiology and Applied Sciences 3(5): 479-486.

Kumar S, Sharma S, Chattopadhyay K (2013) The potential health benefit of polyisoprenylated benzophenones from Garcinia and related genera: Ethnobotanical and therapeutic importance. Fitoterapia 89: 86-125.

Lekshmi NM, Kavya Satheesh SK, Sreejith PP, Rameshkumar KB (2020) Antiproliferative activity of caged xanthones from the leaves of Garcinia wightii T.Anderson. Filoterapia 143: 104592.

Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW (2007) The p63/p73 network mediates chemo-sensitivity to cisplatin in a biologically defined subset of primary breast cancers. Journal of Clinical Investigation 117(5): 1370-1380.

Ling CY, Julia S (2012) Diversity of the tree flora in Semenggoh Arboretum, Sarawak, Borneo. Gardens’ Bulletin Singapore 64(1): 139-169.

Pabla SS, Pabla SS (2008) Real-time polymerase chain reaction: A revolution in diagnostics. Resonance 13: 369-377.

Patil MM, Appaiah KAA (2015) Garcinia: Bioactive compounds and health benefits. Introduction to Functional Food Science 4: 110-125.

Promega (2018) Cell health assays [Online]. Available at:http://www.promega.com/CellHealth [Accessed 3: December 2018].

Qiagen (2013) RNA isolation and purification from cell lines[Online]. Available at:http://compbio.dfci.harvard.edu/compbio/research/labprotocols/contentBlocks/0/contentBlock_files/file16/RNA_Isolation_and_Purification_from_Cell_Lines_Using_Qiagen.pdf [Accessed: 18 December 2018].

Reboucas EDL, Costa JJDN, Passos MJ, Passos JRDS, Hurk RVD, Silva JRV (2013) Real time PCR and importance of housekeeping genes for normalization and quantification of mRNA expression in different tissues. Brazilian Archives of Biology and Technology 56(1): 143-154.

Repin R, Majuakim L, Suleiman M, Nilus R, Mujih H, Gunsalam G (2012) Checklist of trees in Crocker Range Park Permanent Research Plot, Sabah, Malaysia. Journal of Tropical Biology and Conservation 9(1): 127-141.

Roger JBK, Mike WR (2006) Cancer Biology (3rd Ed). England, Pearson Education Limited.

Sethi G Chatterjee S, Rajendran P, Li F, Shanmugam MK, Wong KF, Kumar AP, Senapati P, Behera AK, Hui KM, Basha J, Natesh N, Luk JM, Kundu TK (2014) Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo. Molecular Cancer 13: 66.

Xiong S, Mu T, Wang G, Jiang X (2014) Mitochondria-mediated apoptosis in mammals. Protein and Cell 5(10): 737-749.

Zhang L, Feng J, Kong S, Wu M, Xi Z, Zhang B, Fu W, Lao Y, Tan H, Xu H (2016) Nujiangexathone A, a novel compound from Garcinia nujiangensis, suppresses cervical cancer growth by targeting hnRNPK. Cancer Letters 380: 447-456.