Hemiasterlin derivative (R)(S)(S)-BF65 and Akt inhibitor MK-2206 synergistically inhibit SKOV3 ovarian cancer cell growth.
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.
School of Pharmacy, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan. Electronic address: r00423010@ntu.edu.tw.
Wei-Ting
WT
Lai
School of Pharmacy, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan. Electronic address: b01403002@ntu.edu.tw.
Kai-Lin
KL
Cheng
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: brcrcr1@unife.it.
Riccardo
R
Baruchello
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: rnd@unife.it.
Riccardo
R
Rondanin
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: mcp@unife.it.
Paolo
P
Marchetti
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: smd@unife.it.
Daniele
D
Simoni
Truswork LLC, Short Hills, NJ, USA. Electronic address: richvain@gmail.com.
Ray M
RM
Lee
School of Pharmacy, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan. Electronic address: jhguh@ntu.edu.tw.
Jih-Hwa
JH
Guh
School of Pharmacy, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan. Electronic address: lhsu@ntu.edu.tw.
Lih-Ching
LC
Hsu
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009842:Oligopeptides; C467070:hemiasterlin; D051057:Proto-Oncogene Proteins c-akt
Akt inhibitor MK-2206; Hemiasterlin derivative (R)(S)(S)-BF65; MAPK and Akt signaling pathways; Ovarian cancer