An indolylquinoline derivative promotes apoptosis in human lung cancer cells by impairing mitochondrial functions

Abstract

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.

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

“…Second, MMP is considered to be the “point of no return” for apoptotic cell death, triggering release of cytochrome c and other proapoptotic factors into the cytoplasm [von Ahsen et al, ]. Once MMP is depolarized, caspase‐3 activation leads to the cleavage of PARP, which are essential steps in apoptosis [Liu et al, ]. Finally, loss of PARP‐1, an enzyme implicated in DNA single‐strand repair mechanisms [Eustermann et al, ], can lead to accumulation of DNA breaks and apoptosis.…”

Synthesis, Structure, Chemical Stability, and In Vitro Cytotoxic Properties of Novel Quinoline-3-Carbaldehyde Hydrazones Bearing a 1,2,4-Triazole or Benzotriazole Moiety

“…Thus, the quinoline ring is utilized in clinically used anticancer drugs, such as camptothecin and its analogues, e.g., topotecan , which are known as topoisomerase inhibitors [ 9 , 10 ] or multitarget kinase inhibitors, including lenvatinib and cabozantib [ 9 ], whereas omipalisib and dactolisib are currently under clinical trials as agents targeting the phosphoinositide 3-kinase (PI3K) [ 9 ]. It is worth noting, however, that the antiproliferative effects of the quinoline-containing compounds may also result from cell cycle arrest [ 11 , 12 , 13 , 14 , 15 ], apoptosis [ 16 , 17 ], DNA intercalation [ 18 , 19 ], inhibition of angiogenesis [ 20 , 21 , 22 ], inhibition of proteasome [ 23 , 24 ], and disruption of tubulin polymerization [ 25 , 26 ].…”

An indolylquinoline derivative activates DNA damage response and apoptosis in human hepatocellular carcinoma cells

“…The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with L-glutamine, sodium pyruvate and 10% fetal bovine serum (FBS) at 37˚C in a humidified atmosphere with 5% CO 2 . The synthetic indolylquinoline, EMMQ, was prepared according to the procedures previously described (8).…”

“…Previously, we reported that a small molecular weight indolylquinoline derivative with connection of indole and quinoline functional groups, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), that reduced the growth of human lung cancer cells through apoptotic death (8). The newly synthetic EMMQ available in the authors' group has not been assessed for preventive, protective and usefulness in different diseases.…”