title: Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells.
abstract: The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.
authors.affiliation: Department of Experimental Therapeutics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Cindy R
authors.initials: CR
authors.lastname: Timme
authors.forename: Mike
authors.initials: M
authors.lastname: Gruidl
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003499:Cyclic S-Oxides; D007211:Indoles; C579095:MCL1 protein, human; C523799:MRK 003; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009944:Organoplatinum Compounds; D011758:Pyrroles; D034741:RNA, Small Interfering; D013830:Thiadiazoles; D051020:bcl-X Protein; D000077150:Oxaliplatin; D053829:Amyloid Precursor Protein Secretases; C520962:obatoclax