Abstract
Aim: AT-101 is a polyphenolic compound with potent anti-apoptotic effects in various cancers. In this study, the possible synergistic cytotoxic and apoptotic effect of trastuzumab/AT-101 combination was investigated in HER2-positive breast cancer cell lines. Materials & methods: SKBR-3, MDA-MB-453 and MCF-10A cell lines were treated with a trastuzumab/AT-101 combination. Synergistic cytotoxicity and apoptosis effects were shown and then PI3K and Akt protein levels were studied. Result: The trastuzumab/AT-101 combination induced synergistic cytotoxicity and apoptosis in both breast cancer cells but not in MCF-10A cells. Combination treatment induced cytotoxicity via inhibiting PI3K/AKT but not the MAPK/ERK pathway. Conclusion: The trastuzumab/AT-101 combination may be a good candidate for patients with trastuzumab-resistant Her2-positive breast cancer and inhibition of the PI3K/AKT pathway may be one of the underlying mechanisms.
Keywords:
AT-101; PI3K/AKT; apoptosis; synergism; trastuzumab.
MeSH terms
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Antineoplastic Agents, Immunological / pharmacology
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Antineoplastic Agents, Immunological / therapeutic use
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Agents, Phytogenic / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Drug Synergism
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Female
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Gossypol / analogs & derivatives*
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Gossypol / pharmacology
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Gossypol / therapeutic use
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Humans
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, ErbB-2 / metabolism
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Signal Transduction / drug effects
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Trastuzumab / pharmacology*
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Trastuzumab / therapeutic use
Substances
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Antineoplastic Agents, Immunological
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Antineoplastic Agents, Phytogenic
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ERBB2 protein, human
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Gossypol
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Trastuzumab
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gossypol acetic acid