Melilotus indicus extract induces apoptosis in hepatocellular carcinoma cells via a mechanism involving mitochondria-mediated pathways

Abstract

Melilotus indicus, is a traditional medicine used as analgesic and emollient. Although Melilotus indicus extract (MIE) has recently been shown to suppress growth of several tumor cell lines, information regarding its antitumor mechanism is completely unknown. Here, we report the mechanism underlying the effects of MIE on human hepatocellular carcinoma cells, specifically HepG2, and SNU-182 cells. Methanolic MIE impaired the proliferation, and induced cell death in both HepG2 and SNU-182 cells but not in normal hepatic L-02 cells. Mechanistically, flow cytometric analysis revealed that MIE induces apoptosis in HepG2, and SNU-182 cells. However, MIE-induced apoptosis were not affected by a pan caspase inhibitor z-VAD-fmk as well as MIE did not stimulate caspase activation. Furthermore we found that MIE-induced apoptosis could be attributed to a mechanism involving mitochondria-mediated pathways evidenced by decrease in the mitochondrial membrane potential (ΔΨm), increase in the Bax/Bcl-2 ratio, and translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. Suppression in AIF expression by siRNA reduced MIE-induced apoptosis which suggested the dependency of MIE on AIF to induce apoptosis in hepatocellular carcinoma cells. To the best of our knowledge this is the first report elucidating the anticancer mechanism of MIE. Our findings suggested that MIE might be a good extract for developing anticancer drugs for human hepatocellular carcinoma treatment.

Anticancer effect of nor-wogonin (5, 7, 8-trihydroxyflavone) on human triple-negative breast cancer cells via downregulation of TAK1, NF-κB, and STAT3

“…On the contrary, anti-apoptotic molecules such as Bcl-2 can prevent the conformational change and oligomerization of Bax and Bak [33, 34]. Furthermore, induction of apoptosis is correlated with an increase in the ratio of proapoptotic/antiapoptotic Bax/Bcl-2 [35, 36]. Our results showed that nor-wogonin treatment downregulated Bcl-2 protein expression and upregulated Bax protein expression, resulting in an increase in Bax/Bcl-2 ratio, which could be a possible mechanism by which nor-wogonin induced a loss in the Δψm.…”

Aplysin Protects Against Alcohol‐Induced Liver Injury Via Alleviating Oxidative Damage and Modulating Endogenous Apoptosis‐Related Genes Expression in Rats

“…Our preceding findings support the idea that in ALD, the major apoptotic signal transduction cascade involves the Bcl‐2 family. Increased Bax and/or decreased Bcl‐2 expression leads to a loss of mitochondrial membrane potential and opening of the mitochondrial permeability transition pores (Abd El‐Hafeez et al., ), which is catastrophic for cells and results in release of cytochrome c into the cytosol. In the cytosol, cytochrome c activates apoptosis by binding and activating the apoptotic protease activating factor 1 (Apaf‐1)–caspase‐9 complex, which forms an apoptosome acts as a processing/activation center for the downstream caspase‐3 (Shahali, Ghanadian, Jafari, & Aghaei, ), leading to poly(ADP‐ribose) polymerase (PARP) cleavage (Gogvadze, Orrenius, & Zhivotovsky, ), and promotes DNA fragmentation, decreases oxygen consumption, and increases ROS, which can ultimately result in the initiation of apoptosis (Li et al., ).…”

Biological Activities of Organic Extracts of the Genus Aristolochia: A Review from 2005 to 2021

“…However, the study lacked the characterization of the bioactive compounds to corroborate their anticancer therapeutic approach [31]. Likewise, in the ME of leaves of the species A. macroura Gomes., the active components were not specifically mentioned and their cytotoxic activity against HepG-2 cells (IC 50 = 0.513 mg/mL) was higher compared to other species such as Schinus molle L. (IC 50 = 0.050 mg/mL) [32].…”