title: Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line.
abstract: Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
authors.forename: Ayunadirah
authors.initials: A
authors.lastname: Ayub
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
authors.forename: Wai Kien
authors.initials: WK
authors.lastname: Yip
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Electronic address: shf@upm.edu.my.
authors.forename: Heng Fong
authors.initials: HF
authors.lastname: Seow
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: C000597236:IGF1R protein, human; D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases
keywords: IGF-1R; MEK; PI3K; Synergism; Triple-negative breast cancer; mTORC