title: Targeting leukemic side population cells by isatin derivatives of nicotinic acid amide.
abstract: Side population (SP) cells mediate chemoresistance in leukemia. However, chemical inhibition approach to target SP cells has been poorly studied. Herein, we report the discovery of isatin derivatives of nicotinic acid amide as potent side population cell inhibitors. The selected derivatives showed superior potency over the reference drug verapamil. Furthermore, the treatment increased chemosensitivity and inhibited the cell proliferation on three different leukemic cell lines, K562, THP-1 and U937, suggesting that both SP and the bulk of leukemic cells are affected. Moreover, treatment with the most potent compound Nic9 reduced the expression of ABCG2, demonstrating that side population inhibition effect of the target derivatives is at least via ABCG2 inhibition. Importantly, the target derivatives induced erythrocyte/dendritic differentiation to leukemic cells mainly through Musashi/Numb pathway modulation.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, Dokki, Cairo, Egypt.
authors.forename: A M
authors.initials: AM
authors.lastname: Naglah
authors.affiliation: Stem Cell and Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital and Research Center, Saudi Arabia.
authors.forename: Z
authors.initials: Z
authors.lastname: Shinwari
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M A
authors.initials: MA
authors.lastname: Bhat
authors.affiliation: Stem Cell and Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital and Research Center, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Al-Tahhan
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M A
authors.initials: MA
authors.lastname: Al-Omar
authors.affiliation: Stem Cell and Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital and Research Center, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Al-Dhfyan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007510:Isatin / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000032:analysis; D009536:Niacinamide / Q000494:pharmacology*; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D058985:Side-Population Cells / Q000187:drug effects*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C484065:NGFR protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D009536:Niacinamide; D007510:Isatin