MK-2206, an Akt inhibitor, enhances carboplatinum/paclitaxel efficacy in gastric cancer cell lines.

Abstract

BACKGROUND:

Several molecularly-targeted agents are being evaluated in gastric cancer cell lines. In this study we evaluated the synergistic potential of MK-2206, an oral potent allosteric Akt inhibitor, in combination with chemotherapeutic agents in human gastric cancer cell lines.

MATERIALS AND METHODS:

We evaluated effects of MK-2206 on cell growth and cell signaling using a panel of gastric cancer cell lines AGS, SNU-1 and SNU 16. The analysis of drug combinations was conducted by using CellTiter-Blue™ Cell Viability Assay which yielded the combination index (CI). MK-2206 and representative chemotherapy agent were further evaluated regarding their effects on Akt inhibition and downstream targets using western blots probed with the appropriate antibodies. We assessed the combination of MK-2206 and chemotherapy in three different treatment sequences.

RESULTS:

We demonstrated in vitro synergistic efficacy of MK-2206 when combined with carboplatinum and paclitaxel in the three cell lines examined. Efficacy was dose dependent. We assessed the combination of MK-2206 and carboplatinum/paclitaxel in three different treatment sequences; 24 h of exposure to combination chemotherapy followed by a 48 h exposure to MK-2206 resulted in the highest synergistic antiproliferative effect in all cell lines. On the other hand, the reverse sequence (MK-2206 followed by chemotherapy) and the concurrent treatment schedule were slightly synergistic or additive as well. The effects of MK-2206 on p-Akt and other downstream targets was reported.

CONCLUSIONS:

Our findings suggest that Akt inhibition augments the efficacy of existing gastric cancer therapeutics (carboplatinum and paclitaxel); thus, MK-2206 is a promising agent to treat gastric cancer patients who receive these cytotoxic agents. The magnitude of synergy depended on the treatment sequence; a schedule of MK-2206 dosed before or concurrently with chemotherapy was not as effective as being dosed after chemotherapy. Further experiments addressing MK-2206's mechanism of action in combination with chemotherapy are needed.

• Authors: Khaldoun Almhanna, Christopher L Cubitt, Shumin Zhang, Sabiha Kazim, Kazim Husain, Daniel Sullivan, Said Sebti, Mokenge Malafa
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 14 Issue 10 Pg. 932-6 (Oct 01 2013) ISSN: 1555-8576 [Electronic] United States
• PMID: 23917345 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Carboplatin
• Proto-Oncogene Proteins c-akt
• Paclitaxel

Topics

• Antineoplastic Agents (pharmacology)
• Carboplatin (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Stomach Neoplasms