Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties

• Published in: Acta pharmacologica Sinica 2019-05, Vol.40 (5), p.689-698
• Main Authors: Liu, Yong-qing, Wang, Shi-kang, Xu, Qing-qing, Yuan, Hui-qing, Guo, Yan-xia, Wang, Qian, Kong, Feng, Lin, Zhao-min, Sun, De-qing, Wang, Rong-mei, Lou, Hong-xiang
• Format: Article
• Language: English
• Subjects: Acid resistance; AKT protein; Animals; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Body weight; Cell growth; Cell Line, Tumor; Cell proliferation; Colon cancer; Docetaxel - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glioma; Humans; Immunology; Inhibition; Internal Medicine; Kinases; Leukemia; Male; Medical Microbiology; Mice, Inbred C57BL; Neoplastic Stem Cells - drug effects; Pharmacology/Toxicology; Phenotypes; Prostate cancer; Prostatic Neoplasms - drug therapy; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Stem cells; Transcription activation; Triterpenes - pharmacology; Triterpenes - therapeutic use; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-018-0157-9

Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC 50 value in anti-proliferation was ∼17 μM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10–30 μM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.