Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model

Zhang, Qianyu1; Zhang, Ying2,3; Wang, Chen2,3; Tang, Huan2,3; Ma, Ang2,3; Gao, Peng2,3; Shi, Qiaoli2,3; Wang, Guohua2,3; Shen, Shengnan2,3; Zhang, Junzhe2,3; Xia, Fei2,3; Zhu, Yinhua4; Wang, Jigang1,2,3,5,6,7

2024-07-01

10.1016/j.phymed.2024.155657

PHYTOMEDICINE   影响因子和分区

0944-7113

1618-095X

Background: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate -limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. Purpose: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. Methods: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity -based protein profiling (ABPP) technology. The target validation was performed by in -gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. Results: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti -cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. Conclusion: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.

Gambogic acid 6-phosphogluconate dehydrogenase Pentose phosphate pathway Activity -based protein profiling Covalent inhibitor

SCI

英语

通讯

Scientific and technological innovation project of China Academy of Chinese Medical Sciences["CI2023D003","CI2021B014"] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002] ; National Key Research and Development Program of China["2020YFA0908000","2022YFC2303603"] ; National Natural Science Foundation of China["82141001","82274182","82074098","82173914"] ; CACMS Innovation Fund["CI2023E002","CI2021A05101","CI2021A05104"] ; Science and Technology Foundation of Shenzhen[JCYJ20210324115800001] ; Shenzhen Medical Research Fund[B2302051] ; Fundamental Research Funds for the Central Public Welfare Research Institutes["ZZ14-YQ-050","ZZ14-YQ-051","ZZ14-YQ-052","ZZ14-FL-002","ZZ14-ND-010","ZZ16-ND-10-16","ZZ15-ND-10","ZZ16-ND-10-23"]

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:001236449400001

ELSEVIER GMBH

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Henan Univ, Sch Pharm, State Key Lab Antiviral Drugs, Kaifeng 475004, Peoples R China
2.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
3.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
4.China Agr Univ, Beijing Adv Innovat Ctr Food Nutr & Human Hlth, Dept Nutr & Hlth, Beijing 100193, Peoples R China
5.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
6.Southern Med Univ, Sch Tradit Chinese Med, Guangzhou 510515, Guangdong, Peoples R China
7.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Dept Urol, Shenzhen 518020, Peoples R China

Zhang, Qianyu,Zhang, Ying,Wang, Chen,et al. Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model[J]. PHYTOMEDICINE,2024,129.

Zhang, Qianyu.,Zhang, Ying.,Wang, Chen.,Tang, Huan.,Ma, Ang.,...&Wang, Jigang.(2024).Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model.PHYTOMEDICINE,129.

Zhang, Qianyu,et al."Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model".PHYTOMEDICINE 129(2024).