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Signal transduction pathways, which regulate cell growth and survival, are up-regulated in many cancers and there is considerable interest in their pharmaceutical modulation for cancer treatment. However inhibitors of single pathway components induce feedback mechanisms that overcome the growth moderating effect of the inhibitor. Combination treatments have been proposed to provide a more complete pathway inhibition. Here the effect of dual treatment of cancer cells with a pan-Akt and a pan-mTOR inhibitor was explored. Breast (SKBr3 and MDA-MB-468) and colorectal (HCT8) cancer cells were treated with the pan-Akt inhibitor MK2206 and pan-mTOR inhibitor AZD8055. Cytotoxic effect of the two drugs were determined using the MTT assay and the Combination Index and isobolomic analysis used to determine the nature of the interaction of the two drugs. Flow cytometry and western blot were employed to demonstrate drug effects on cell cycle distribution and phosph-Aktser473 expression. Radiolabelled ([methyl-3H]) Choline uptake was measured in control and drug-treated cells to determine the modulatory effects of the drugs on choline incorporation. The two drugs acted synergistically to inhibit the growth rate of each cancer cell line. Flow cytometry demonstrated G0/G1 blockade with MK2206 and AZD8055 which was greater when cells were treated with both drugs. The incorporation of [methyl-3H] choline was found be decreased to a greater extent in cells treated with both drugs compared with cells treated with either drug alone. Conclusions Pan-mTOR and pan-Akt inhibition may be highly effective in cancer treatment and measuring changes in choline uptake could be useful in detecting efficacious drug combinations.

Original publication

DOI

10.1007/s10637-018-0642-5

Type

Journal article

Journal

Invest New Drugs

Publication Date

06/2019

Volume

37

Pages

424 - 430

Keywords

Akt, Breast cancer, Cell cycle, Combination index, Radiolabelled choline, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Breast Neoplasms, Cell Cycle, Cell Proliferation, Choline, Colonic Neoplasms, Drug Synergism, Female, Heterocyclic Compounds, 3-Ring, Humans, Morpholines, Phosphorylation, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases, Tumor Cells, Cultured