title: Cytotoxic activity and apoptosis-inducing potential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivatives.
abstract: Anticancer role of andrographolide is well documented. To find novel potent derivatives with improved cytotoxicity than andrographolide on cancer cells, two series of di-spiropyrrolidino- and di-spiropyrrolizidino oxindole andrographolide derivatives prepared by cyclo-addition of azomethine ylide along with sarcosine or proline (viz. sarcosine and proline series respectively) and substitution of different functional groups (-CH3, -OCH3 and halogens) were examined for their cytotoxic effect on a panel of six human cancer cell lines (colorectal carcinoma HCT116 cells, pancreatic carcinoma MiaPaCa-2 cells, hepatocarcinoma HepG2 cells, cervical carcinoma HeLa cells, lung carcinoma A549 and melanoma A375 cells). Except halogen substituted derivatives of proline series (viz. CY2, CY14 and CY15 for Br, Cl and I substitution respectively), none of the other derivatives showed improved cytotoxicity than andrographolide in the cancer cell lines examined. Order of cytotoxicity of the potent compounds is CY2>CY14>CY15>andrographolide. Higher toxicity was observed in HCT116, MiaPaCa-2 and HepG2 cells. CY2, induced death of HCT116 (GI50 10.5), MiaPaCa-2 (GI50 11.2) and HepG2 (GI50 16.6) cells were associated with cell rounding, nuclear fragmentation and increased percentage of apoptotic cells, cell cycle arrest at G1 phase, ROS generation, and involvement of mitochondrial pathway. Upregulation of Bax, Bad, p53, caspases-3,-9 and cleaved PARP; downregulation of Bcl-2, cytosolic NF-κB p65, PI3K and p-Akt; translocation of P53/P21, NF-κB p65 were seen in CY2 treated HCT116 cells. Thus, three halogenated di-spiropyrrolizidino oxindole derivatives of andrographolide are found to be more cytotoxic than andrographolide in some cancer cells. The most potent derivative, CY2 induced death of the cancer cells involves ROS dependent mitochondrial pathway like andrographolide.
authors.affiliation: Cancer and Cell Biology Division, CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India.
authors.forename: Sumit Kumar
authors.initials: SK
authors.lastname: Dey
authors.forename: Dipayan
authors.initials: D
authors.lastname: Bose
authors.forename: Abhijit
authors.initials: A
authors.lastname: Hazra
authors.forename: Subhendu
authors.initials: S
authors.lastname: Naskar
authors.forename: Abhishek
authors.initials: A
authors.lastname: Nandy
authors.forename: Rudra Narayan
authors.initials: RN
authors.lastname: Munda
authors.forename: Subhadip
authors.initials: S
authors.lastname: Das
authors.forename: Nabanita
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Nirup Bikash
authors.initials: NB
authors.lastname: Mondal
authors.forename: Sukdeb
authors.initials: S
authors.lastname: Banerjee
authors.forename: Krishna Das
authors.initials: KD
authors.lastname: Saha
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial; D008956:Models, Chemical; D000078183:Oxindoles; D017382:Reactive Oxygen Species
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D007211:Indoles; D000078183:Oxindoles; D017382:Reactive Oxygen Species; C022960:2-oxindole; C030419:andrographolide