Hemiasterlin derivative (R)(S)(S)-BF65 and Akt inhibitor MK-2206 synergistically inhibit SKOV3 ovarian cancer cell growth
Journal
Biochemical Pharmacology
Journal Volume
113
Pages
12-23
Date Issued
2016
Author(s)
Abstract
We reported previously that a hemiasterlin derivative BF65 is a potent anticancer agent that can inhibit microtubule assembly. Here we show that a more potent stereospecific diastereomer (R)(S)(S)-BF65 can synergize with an allosteric Akt inhibitor MK-2206 to suppress the growth of SKOV3 ovarian cancer cells with constitutively active Akt. (R)(S)(S)-BF65 induced mitotic arrest and MK-2206 caused G0/G1 arrest, while the combination of both induced simultaneous G0/G1 and G2/M cell cycle arrest. (R)(S)(S)-BF65 induced phosphorylation and inactivation of Bcl-2, and downregulated Mcl-1, consequently may lead to apoptosis. (R)(S)(S)-BF65 inhibited mitogen-activated protein kinases (MAPKs), which may stimulate cell proliferation upon activation. (R)(S)(S)-BF65 also induced DNA damage after long-term treatment. MK-2206 is known to inhibit phosphorylation and activation of Akt and suppress cancer cell growth. The combination of (R)(S)(S)-BF65 and MK-2206 also inhibited the Akt pathway. Interestingly, MK-2206 upregulated Bcl-2 and induced activation of MAPKs in SKOV3 cells; however, when combined with (R)(S)(S)-BF65, these prosurvival effects were reversed. The combination also more significantly decreased Mcl-1 protein, increased PARP cleavage, and induced γ-H2AX, a DNA damage marker. Remarkably, MK-2206 enhanced the microtubule depolymerization effect of (R)(S)(S)-BF65. The combination of (R)(S)(S)-BF65 and MK-2206 also markedly inhibited cell migration. Thus, MK-2206 synergizes with (R)(S)(S)-BF65 to inhibit SKOV3 cell growth via downregulating the Akt signaling pathway, and enhancing the microtubule disruption effect of (R)(S)(S)-BF65. (R)(S)(S)-BF65 in turn suppresses Bcl-2 and MAPKs induced by MK-2206. (R)(S)(S)-BF65 and MK-2206 compensate each other leading to increased apoptosis and enhanced cytotoxicity, and may also suppress cancer cell invasion. ? 2016 Elsevier Inc.
SDGs
Other Subjects
1,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; antineoplastic agent; bf 65; cyclin B1; docetaxel; gamma tubulin; histone H2AX; histone H3; mitogen activated protein kinase; mitogen activated protein kinase p38; mpm2 protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; paclitaxel; polo like kinase 1; protein; protein Bak; protein bcl 2; protein kinase B; protein mcl 1; unclassified drug; vincristine; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; antineoplastic agent; fused heterocyclic rings; hemiasterlin; oligopeptide; protein kinase B; apoptosis; Article; cancer inhibition; cytotoxicity; depolymerization; DNA damage; DNA fragmentation; down regulation; drug potentiation; female; flow cytometry; G1 phase cell cycle checkpoint; G2 phase cell cycle checkpoint; human; human cell; immunofluorescence; M phase cell cycle checkpoint; microtubule; ovary cancer; priority journal; protein cleavage; protein phosphorylation; signal transduction; Western blotting; antagonists and inhibitors; cell cycle checkpoint; cell proliferation; cell survival; chemistry; drug effects; metabolism; ovary tumor; pathology; stereoisomerism; tumor cell line; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Heterocyclic Compounds, 3-Ring; Humans; Oligopeptides; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; Stereoisomerism
Type
journal article