Jianpi Decoction Combined with Medroxyprogesterone Acetate Alleviates Cancer Cachexia and Prevents Muscle Atrophy by Directly Inhibiting E3 Ubiquitin Ligase

Qi Li; Zhao-di Kong; Huan Wang; Hong-Hui Gu; Zhong Chen; Shi-Guang Li; Yi-Qi Chen; Yu Cai; Zhen-Jiang Yang

doi:10.1007/s11655-023-3702-4

Jianpi Decoction Combined with Medroxyprogesterone Acetate Alleviates Cancer Cachexia and Prevents Muscle Atrophy by Directly Inhibiting E3 Ubiquitin Ligase

Chin J Integr Med. 2023 Aug 24. doi: 10.1007/s11655-023-3702-4. Online ahead of print.

Authors

Qi Li^#¹, Zhao-di Kong^#², Huan Wang², Hong-Hui Gu¹, Zhong Chen¹, Shi-Guang Li¹, Yi-Qi Chen¹, Yu Cai^{2

3}, Zhen-Jiang Yang⁴

Affiliations

¹ Department of Oncology and Hematology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, 518033, China.
² College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, 510632, China.
³ Guangdong Key Lab of Traditional Chinese Medicine Information Technology, Jinan University, Guangzhou, 510632, China.
⁴ Department of Oncology and Hematology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, 518033, China. dzjysz@163.com.

^# Contributed equally.

PMID: 37612478
DOI: 10.1007/s11655-023-3702-4

Abstract

Objective: To provide comprehensive evidence for the anti-cancer cachexia effect of Jianpi Decoction (JP) and to explore its mechanism of anti-cancer cachexia.

Methods: A mouse model of colon cancer (CT26)-induced cancer cachexia (CC) was used to investigate the anti-CC effect of JP combined with medroxyprogesterone acetate (MPA). Thirty-six mice were equally divided into 6 groups: normal control, CC, MPA (100 mg•kg^-1•d^-1), MPA + low-dose (20 mg•kg^-1•d^-1) JP (L-JP), MPA + medium-dose (30 mg•kg^-1•d^-1) JP (M-JP), and MPA + high-dose (40 mg•kg^-1•d^-1) JP (H-JP) groups. After successful modeling, the mice were administered by gavage for 11 d. The body weight and tumor volume were measured and recorded every 2 d starting on the 8th day after implantation. The liver, heart, spleen, lung, kidney, tumor and gastrocnemius muscle of mice were collected and weighed. The pathological changes of the tumor was observed, and the cross-sectional area of the gastrocnemius muscle was calculated. The protein expressions of STAT3 and E3 ubiquitinase in the gastrocnemius muscle were measured by Western blot. In addition, an in vitro C2C12 myotube formation model was established to investigate the role of JP in hindering dexamethasone-induced muscle atrophy. In vitro experiments were divided into control, model, and JP serum groups. After 2-d administration, microscopic photographs were taken and myotube diameters were calculated. Western blot was performed to measure the protein expressions of STAT3 and E3 ubiquitinase.

Results: JP combined with MPA restored tumor-induced weight loss (P<0.05, vs. CC) and muscle fiber size (P<0.01, vs. CC). Mechanistically, JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx in tumor-induced muscle atrophy in vivo (P<0.05, vs. CC). In addition, JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx and p-STAT3 phosphorylation (P<0.05 or P<0.01 vs. model group) in C2C12 myotubes treated with dexamethasone in vitro.

Conclusions: Administration of JP combined with MPA restores tumor-induced cachexia conditions. In addition, the profound effect of JP combined with MPA on tumor-induced cachexia may be due to its inhibition of muscle proteolysis (E3 ubiquitinase system).

Keywords: Chinese medicine; E3 ubiquitin ligases; Jianpi Decoction; cancer cachexia; muscle atrophy.