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

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 IC 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.

<p>Acetyl-11-keto-β-boswellic Acid Inhibits Precancerous Breast Lesion MCF-10AT Cells via Regulation of LINC00707/miR-206 that Reduces Estrogen Receptor-α</p>

“…15 Liu indicated that AKBA inhibits the proliferation and cancer stem cell-like properties of docetaxel resistant prostate cancer cells in vitro and in vivo via blocking Akt and Stat3 signaling. 16 However, the potential therapeutic effect and the underlying molecular mechanism of AKBA on breast tumor have yet to be elucidated.…”

Acetyl-11-keto-β-boswellic acid inhibits proliferation and induces apoptosis of gastric cancer cells through the phosphatase and tensin homolog /Akt/ cyclooxygenase-2 signaling pathway

“…Our animal experiments verified the findings of in vitro experiments. Previous research confirmed that AKBA has an anti-tumor effect in nude mice[ 2 - 4 , 33 , 42 , 43 ]. Our results indicate that the tumor size of AKBA-treated nude mice is significantly smaller compared to the control group.…”

“…The molecular structure of AKBA is shown in Figure 1 . AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors, such as hepatocellular carcinoma[ 2 ], glioblastoma[ 3 ], prostate cancer[ 4 ], lung carcinogenesis[ 5 ], colon cancer[ 6 , 7 ], and leukemia[ 8 , 9 ]. However, the efficacy and mechanism of action of AKBA in treating gastric cancer have not been studied.…”

An Update on Pharmacological Potential of Boswellic Acids against Chronic Diseases

“…In another study, AKBA was found responsible for the suppression of VEGFR2-mediated angiogenesis in prostate cancer [101]. Studies by Liu et al, showed that AKBA suppressed docetaxel-resistant prostate cancer cells via blockage of STAT3 and Akt signaling pathways [138]. A semi-synthetic triterpenoid derivative, 3-cinnamoyl-11-keto-beta-BA (C-KβBA), demonstrated specific antiproliferative and proapoptotic effects in cancer cell lines such as PC-3, LnCaP, and DU-145, as well as in PC-3 prostate cancer xenografts, by downregulating the activation of p70 ribosomal S6 kinase [122].…”