DC-81-Indole conjugate agent induces mitochondria mediated apoptosis in human melanoma A375 cells.
DC-81, an antitumor antibiotic produced by the Streptomyces species, belongs to pyrrolo[2,1-c] [1,4]benzodiazepine (PBD), which are potent inhibitors of nucleic acid synthesis. We previously reported an efficient synthesis of PBD hybrids linked with indole carboxylates. This is the first demonstration on the mechanism of the anticancer effect of PBD hybrid (IN6CPBD) agent on human melanoma A375 cells. IN6CPBD-treated cells exhibited higher cytotoxicity than DC-81 and displayed several features of apoptosis, including an increase in the sub-G1 population, a significantly increased annexin V binding, a degradation of caspase-3, and poly (ADP-ribose) polymerase (PARP) cleavage. Because degradative changes associated with apoptosis are often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in IN6CPBD-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with IN6CPBD resulted in the loss of mitochondrial membrane potential (DeltaPsimt), a decrease in intracellular pH (pHi), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and cytochrome c release. Collectively, our studies indicate that IN6CPBD induces apoptosis in A375 cells through a mitochondrial dysfunction pathway, leading to caspase-3 substrate PARP cleavage and subsequent apoptotic cell death.
Hu
Wan-Ping
WP
Faculty of Biotechnology and Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yu
Hsin-Su
HS
Sung
Ping-Jyun
PJ
Tsai
Feng-Yuan
FY
Shen
Yu-Kai
YK
Chang
Long-Sen
LS
Wang
Jeh-Jeng
JJ
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024161:Collagen Type XI / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004147:Dioxins / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009696:Nucleic Acids / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
C474072:(11aS)-8-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5-one; C467956:2,4,5,7,8-pentamethyl-4H-1,3-benzodioxin-6-ol; D000970:Antineoplastic Agents; D001381:Azepines; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D004147:Dioxins; C523952:IN6CPBD; D007211:Indoles; D009696:Nucleic Acids; D009840:Oligomycins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D001569:Benzodiazepines; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D002374:Catalase; D013482:Superoxide Dismutase; D053148:Caspase 3