title: Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.
abstract: Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Sivapriya
authors.initials: S
authors.lastname: Ponnurangam
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Dandawate
authors.affiliation: Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Animesh
authors.initials: A
authors.lastname: Dhar
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Ossama W
authors.initials: OW
authors.lastname: Tawfik
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Rajashri R
authors.initials: RR
authors.lastname: Parab
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Prabhu Dutt
authors.initials: PD
authors.lastname: Mishra
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Prafull
authors.initials: P
authors.lastname: Ranadive
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weir
authors.affiliation: Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Sugumar
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Roy A
authors.initials: RA
authors.lastname: Jensen
authors.affiliation: Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Interdisciplinary Science and Technology Research Academy, Abeda Inamdar Senior College, Azam Campus, Pune, 411001, India.
authors.forename: Subhash B
authors.initials: SB
authors.lastname: Padhye
authors.affiliation: Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.|The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D000089742:Doublecortin-Like Kinases; D019008:Drug Resistance, Neoplasm; D004448:Echinomycin / Q000494:pharmacology*; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D004448:Echinomycin; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: DCLK1; Hes1; NICD; apoptosis; tumor xenograft