title: SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo.
abstract: Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
authors.affiliation: Department of Oncology & Pathology, Cancer Center Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden; Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. Electronic address: chern.oon@usm.my.
authors.forename: Chern Ein
authors.initials: CE
authors.lastname: Oon
authors.affiliation: Department of Oncology & Pathology, Cancer Center Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Strell
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.
authors.forename: Keng Yoon
authors.initials: KY
authors.lastname: Yeong
authors.affiliation: Department of Oncology & Pathology, Cancer Center Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Department of Oncology & Pathology, Cancer Center Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden; Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Zuidhorst building, ZH254, 7500AE Enschede, The Netherlands. Electronic address: j.prakash@utwente.nl.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000093542:Gemcitabine
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D003841:Deoxycytidine; D056564:Sirtuin 1; D000093542:Gemcitabine
keywords: 6-Chloro-2,3,4,9-tetrahydro-1H-Carbazole-1-carboxamide (EX527) (PubChem CID: 5113032); EX527; Gemcitabine; Pancreatic cancer; SIRT1; Sirtuin; Tumour resistance