cytochrome-c-t and indole

The World Health Organization reported that approximately 324,000 new cases of melanoma skin cancer were diagnosed worldwide in 2020. The incidence of melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical models and clinical trials. Some naturally occurring products and synthetic derivatives are apoptosis inducers and may represent a realistic option in the fight against the disease. Thus, chalcones have received considerable attention due to their potential cytotoxicity against cancer cells. We have previously reported a chalcone containing an indole and a pyridine heterocyclic rings and an α-bromoacryloylamido radical which displays potent antiproliferative activity against several tumor cell lines. In this study, we report that this chalcone is a potent apoptotic inducer for human melanoma cell lines SK-MEL-1 and MEL-HO. Cell death was associated with mitochondrial cytochrome

Topics: Apoptosis; Caspases; Cell Death; Cell Line, Tumor; Chalcones; Cytochromes c; Humans; Indoles; Melanoma; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction

A number of effective anti-cancer drugs contain either indole or quinoline group. Compounds fused indole and quinoline moieties altogether as indolylquinoline were rarely reported as anti-cancer agents. We reported here that a synthetic indolylquinoline derivative, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), inhibited the growth of human non-small cell lung cancer (NSCLC) cells in dose- and time-dependent manners. The cytotoxicity was mediated through apoptotic cell death that began with mitochondrial membrane potential interruption and DNA damage. EMMQ caused transient elevation of p53 that assists in cytochrome c release, cleavage of downstream PARP and procaspase-3 and mitochondria-related apoptosis. The degree of apoptotic cell death depends on the status of tumor suppressor p53 of the target cells. H1299 cells with stable ectopic expression of p53 induced cytotoxicity by disrupting mitochondria functions that differed with those transfected with mutant p53. Knocking-down of p53 attenuated drug effects. EMMQ suppressed the growth of A549 tumor cells in xenograft tumors by exhibiting apoptosis characteristics. Given its small molecular weight acting as an effective p53 regulator in NSCLC cells, EMMQ could be an addition to the current list of lung cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cytochromes c; DNA Damage; Humans; Indoles; Lung Neoplasms; Mitochondria; Quinolines; Tumor Suppressor Protein p53

In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.

Topics: Alkaloids; Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Cell Nucleus; Cytochromes c; Cytoskeleton; DNA Fragmentation; Drug Screening Assays, Antitumor; Enzyme Activation; Gene Expression Regulation, Neoplastic; Glutathione Reductase; Humans; Indole Alkaloids; Indoles; Magnetic Resonance Spectroscopy; Male; Membrane Potential, Mitochondrial; Models, Biological; Plant Bark; Prostatic Neoplasms; Quinolizidines; Reactive Oxygen Species; Terpenes