Inhibition of CDK2/CyclinE1 by Xanthones from the Mangosteen (): a Structure-activity Relationship Study

Overview

Journal Nat Prod Res

Specialty Biology

Date 2020 Jul 22

PMID 32691623

Citations 2

Authors

Mirielle C Nauman

Restituto Tocmo

Bhaskar Vemu

Jacob P Veenstra

Jeremy J Johnson

Affiliations

Soon will be listed here.

Abstract

Uncontrolled regulation of cyclin dependent kinases (CDKs) has negative implications in many cancers and malignancies and has recently led to the approval of select CDK inhibitors. Herein we present data reporting that xanthones, a class of compounds isolated from the purple mangosteen () fruit, can inhibit CDK2/CyclinE1. We evaluated nine different xanthones, including α-mangostin, β-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C, garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin for toxicity in 22Rν1 (prostate cancer cells) and MDA-MB-231 (breast cancer cells). All compounds dose-dependently inhibited the viability of both cell lines. A cell free biochemical assay was performed to determine if selected phytochemicals inhibited CDK2/CyclinE1. γ-Mangostin and α-mangostin were the strongest inhibitors, respectively. The results suggest that the position of key functional groups including hydroxyl and isoprenyl groups contribute to the CDK2 inhibitory effect. Taken together, the evidence suggests that xanthones can directly target CDK2 providing a possible explanation for their therapeutic potential.

Citing Articles

α-Mangostin Promotes In Vitro and In Vivo Degradation of Androgen Receptor and AR-V7 Splice Variant in Prostate Cancer Cells.

Nauman M, Won J, Petiwala S, Vemu B, Lee H, Sverdlov M Cancers (Basel). 2023; 15(7).

PMID: 37046780 PMC: 10093438. DOI: 10.3390/cancers15072118.

The purple mangosteen (Garcinia mangostana): Defining the anticancer potential of selected xanthones.

Nauman M, Johnson J Pharmacol Res. 2021; 175:106032.

PMID: 34896543 PMC: 9597473. DOI: 10.1016/j.phrs.2021.106032.

References

Whittaker S, Mallinger A, Workman P, Clarke P . Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther. 2017; 173:83-105. PMC: 6141011. DOI: 10.1016/j.pharmthera.2017.02.008. View

Zheng Y, Wang H, Yang M, Peng G, Dong T, Xu M . Prenylated Flavonoids from Roots of Glycyrrhiza uralensis Induce Differentiation of B16-F10 Melanoma Cells. Int J Mol Sci. 2018; 19(8). PMC: 6122034. DOI: 10.3390/ijms19082422. View

Kurose H, Shibata M, Iinuma M, Otsuki Y . Alterations in cell cycle and induction of apoptotic cell death in breast cancer cells treated with α-mangostin extracted from mangosteen pericarp. J Biomed Biotechnol. 2012; 2012:672428. PMC: 3332218. DOI: 10.1155/2012/672428. View

Li G, Thomas S, Johnson J . Polyphenols from the mangosteen (Garcinia mangostana) fruit for breast and prostate cancer. Front Pharmacol. 2013; 4:80. PMC: 3693070. DOI: 10.3389/fphar.2013.00080. View

Gutierrez-Orozco F, Failla M . Biological activities and bioavailability of mangosteen xanthones: a critical review of the current evidence. Nutrients. 2013; 5(8):3163-83. PMC: 3775248. DOI: 10.3390/nu5083163. View

Malumbres M, Barbacid M . To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2002; 1(3):222-31. DOI: 10.1038/35106065. View

Petiwala S, Li G, Ramaiya A, Kumar A, Gill R, Saksena S . Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to α-mangostin in C57BL/6 mice. Nutr Res. 2014; 34(4):336-45. PMC: 6298434. DOI: 10.1016/j.nutres.2014.03.002. View

Chin Y, Kinghorn A . Structural Characterization, Biological Effects, and Synthetic Studies on Xanthones from Mangosteen (Garcinia mangostana), a Popular Botanical Dietary Supplement. Mini Rev Org Chem. 2011; 5(4):355-364. PMC: 3090081. DOI: 10.2174/157019308786242223. View

Ramaiya A, Li G, Petiwala S, Johnson J . Single dose oral pharmacokinetic profile of α-mangostin in mice. Curr Drug Targets. 2012; 13(14):1698-704. DOI: 10.2174/138945012804545524. View

10.

Suthammarak W, Numpraphrut P, Charoensakdi R, Neungton N, Tunrungruangtavee V, Jaisupa N . Antioxidant-Enhancing Property of the Polar Fraction of Mangosteen Pericarp Extract and Evaluation of Its Safety in Humans. Oxid Med Cell Longev. 2016; 2016:1293036. PMC: 5040814. DOI: 10.1155/2016/1293036. View

11.

Li G, Petiwala S, Yan M, Won J, Petukhov P, Johnson J . Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer. Mol Nutr Food Res. 2016; 60(6):1458-69. DOI: 10.1002/mnfr.201600037. View

12.

Pham V, Rendon R, Le V, Tippin M, Fu D, Le T . Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy. Mol Carcinog. 2019; 59(2):193-201. PMC: 6946862. DOI: 10.1002/mc.23140. View

13.

Ibrahim S, Abdallah H, El-Halawany A, Nafady A, Mohamed G . Mangostanaxanthone VIII, a new xanthone from Garcinia mangostana and its cytotoxic activity. Nat Prod Res. 2018; 33(2):258-265. DOI: 10.1080/14786419.2018.1446012. View

14.

Lee H, Jang H, Kim H, Shin S, Choo G, Park Y . Antitumor and apoptosis-inducing effects of α-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.)in YD-15 tongue mucoepidermoid carcinoma cells. Int J Mol Med. 2016; 37(4):939-48. PMC: 4790674. DOI: 10.3892/ijmm.2016.2517. View

15.

Ding Y, Luan J, Fan Y, Olatunji O, Song J, Zuo J . α-Mangostin reduced the viability of A594 cells in vitro by provoking ROS production through downregulation of NAMPT/NAD. Cell Stress Chaperones. 2020; 25(1):163-172. PMC: 6985413. DOI: 10.1007/s12192-019-01063-2. View

16.

Johnson J, Petiwala S, Syed D, Rasmussen J, Adhami V, Siddiqui I . α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth. Carcinogenesis. 2011; 33(2):413-9. PMC: 3271271. DOI: 10.1093/carcin/bgr291. View

17.

Wang Y, Chen Y, Cheng X, Zhang K, Wang H, Liu B . Design, synthesis and biological evaluation of pyrimidine derivatives as novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in breast cancer cells. Bioorg Med Chem. 2018; 26(12):3491-3501. DOI: 10.1016/j.bmc.2018.05.024. View

18.

Vemu B, Nauman M, Veenstra J, Johnson J . Structure activity relationship of xanthones for inhibition of Cyclin Dependent Kinase 4 from mangosteen (Garcinia mangostana L.). Int J Nutr. 2019; 4(2):38-45. PMC: 6667231. View

19.

Otto T, Sicinski P . Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017; 17(2):93-115. PMC: 5345933. DOI: 10.1038/nrc.2016.138. View

20.

Preusser M, De Mattos-Arruda L, Thill M, Criscitiello C, Bartsch R, Ruhstaller T . CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. ESMO Open. 2018; 3(5):e000368. PMC: 6109817. DOI: 10.1136/esmoopen-2018-000368. View