3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase

Abstract

BackgroundGlioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.MethodsThe effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.ResultsAKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.ConclusionsTaken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0805-4) contains supplementary material, which is available to authorized users.

<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>

“…10,11 Recently, AKBA was also found to exhibit antitumor effects in human cell lines established from prostate cancer, breast cancer and glioblastoma. [12][13][14] Csuk et al demonstrated that boswellic acid and its derivatives induce apoptosis in breast and cervical cancers cells. 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.…”

Efficient Synthesis and Biological Evaluation of 2,4‐Diaminothieno[2,3‐d]pyrimidine Derivative

“…For the compounds 5 a‐5 o anticancer activity were preliminarily evaluated against Hepatocellular carcinoma (HepG2), Epidermoid Carcinoma‐2 (HEp‐2) and breast cancer (MCF‐7) cell lines in vitro by using standard 2‐(2‐ methoxyl‐4‐nitrophenyl)‐3‐(4‐nitrophenyl)‐5‐(2,4‐disulfonyl‐benzene)‐2H‐tetrazolium monosodium salt (CCK8) assay after exposure of cells to the tested compounds for 48 h (with gefitinib and cisplatin as the reference drug against HEp‐2 cell lines) ,. The results expressed as halfmaximal inhibitory concentration (IC 50 ) values, are presented in Table .…”

Boswelliaextrakte/Boswelliasäuren bei malignen Tumoren: Eine Übersicht

“…Die g2/m-Phase des Zellzyklus ist gekennzeichnet durch die Zweiteilung des Zellkerns (Mitose). Eine Arretierung des Zellzyklus in der G2/M-Phase wurde an Gliomazellen durch AKBA [24] über verschiedene Wege beobachtet und zwar über eine "Downregulation" des Aurora B/TOP2A-sowie über die Regulation des p21/ FOXM1/Cyclin B1-Signalweges.…”

“…Untersucht wurde deren Wirkung auf die Caspasen 1, 3, 8, 9. Wie zu erwarten war, fand sich bei AKBA eine Aktivierung der Apoptose bei Hep G2-Zellen [29] und Glioblastomzellen [24]. Eine Aktivierung der Caspasen 3, 8, 9 und damit der Apoptose bei Hep G2-Zellen wurde auch bei Verwendung von KBA festgestellt [29].…”