title: Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives.
abstract: Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide-hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide-hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60-6.50 μM) on comparison with all other coumarin hydrazide-hydrazone derivatives (CHHD), whereas BCHHD's 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHD's were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt. Electronic address: tamerhefni@yahoo.com.
authors.forename: Tamer
authors.initials: T
authors.lastname: Nasr
authors.affiliation: Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt; Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia.
authors.forename: Samir
authors.initials: S
authors.lastname: Bondock
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Egypt.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Youns
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D006835:Hydrazones; C030123:coumarin; D053148:Caspase 3; D053179:Caspase 7
keywords: Antiproliferative; Apoptosis; Caspases 3/7; Coumarin; Hydrazide–hydrazone; Microarray