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

Abstract

Human liver cancer is one of the most frequently diagnosed cancers worldwide. The development of resistance to therapy limits the application against the disease. To improve treatment, new effective anticancer agents are constantly pursued. Previously, we reported that an indolylquinoline, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), is effective in suppressing the growth of human lung cancer by impairing mitochondria functions. The present study revealed that EMMQ inhibited cell growth and induced apoptosis in liver cancer cells, but not in normal cells. This study demonstrated that EMMQ induced DNA damage by activating p53 and γ-H2AX and cell arrest by suppressing cyclin D1 and CDK2. Damaged DNA injured mitochondrial functions by lowering the membrane potential and producing reactive oxygen species. The subsequent mitochondrial cytochrome c release attenuated pro-survival signals and increased apoptotic characteristics. Introduction of p53 shRNA abrogated drug effects by reducing DNA damage while maintaining mitochondria integrity. In brief, the study demonstrates that the effectiveness of EMMQ accentuated apoptosis of hepatocarcinoma cells by activating p53. Based on these collective findings, the study offered a new perspective of EMMQ that was shown to be a promising candidate to treat liver cancer.

Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition

“…These findings indicate that induction of apoptosis is highly dependent on the concentration of the drugs as well as the individual susceptibility of the HCC cells. Indeed, extensive literature has disclosed that different HCC cell lines experienced different sensitivity to the induction of apoptosis [31][32][33].…”

Myricetin Induces Apoptosis of Human Anaplastic Thyroid Cancer Cells via Mitochondria Dysfunction

“…Apoptosis is programmed cell death Chromatin condensation is a morphological hall marker of apoptotic cell death and DNA damage can induce cell death which leads to a cell cycle arrest (11). The cell cycle involves a series of events that take place within a cell that lead to its division and duplication, resulting in the production of two daughter cells.…”

Chemotherapy for hepatocellular carcinoma: The present and the future

“…It’s necessary to mention drugs that have been studied in vitro and in vivo with promising results, awaiting for trials on humans. Some examples are ursolic acid derivates[ 101 ] and a B5G9[ 102 ] (piperazidine derivative of 23-hydroxy betulinic acid), that cause ROS-mediated apoptosis in HCC cells, EMMQ[ 103 ] (an indolylquinoline derivative), that causes DNA damage by activating p53 and γ-H2AX, and GL63[ 104 ] (a curcumine analogue), which was able to suppress the proliferation of HCC cells by inhibition of the JAK2/STAT3 signaling pathway. Even Valproic Acid[ 105 ], a well-known antiepileptic drug, showed potential anti-HCC effect in vitro by promotion of epithelial mesenchymal transition of hepatocarcinoma cells via transcriptional and post-transcriptional up regulation of Snail.…”