Article

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

Authors: Yong-qing Liu1,2, Shi-kang Wang3, Qing-qing Xu4,5,6, Hui-qing Yuan5,6, Yan-xia Guo5, Qian Wang6, Feng Kong5, Zhao-min Lin5, De-qing Sun1, Rong-mei Wang1, Hong-xiang Lou2
1 Department of Pharmacy, The Second Hospital of Shandong University, Jinan 250033, China
2 Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
3 Emergency Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China
4 Department of Dermato- venereology, The Second Hospital of Shandong University, Jinan 250033, China
5 Central Research Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
6 Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, China
Correspondence to: Rong-mei Wang: rongmeiwang@hotmail.com, Hong-xiang Lou: louhongxiang@sdu.edu.cn,
DOI: 10.1038/s41401-018-0157-9
Received: 5 February 2018
Accepted: 3 July 2018
Advance online: 31 August 2018

Abstract

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 IC50 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.
Keywords: acetyl-11-keto-β-boswellic acid; prostate cancer; docetaxel-resistance; chemoresistant stem cell-like properties; Akt; Stat3

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