Mukonal exerts anticancer effects on the human breast cancer cells by inducing autophagy and apoptosis and inhibits the tumor growth in vivo

Abstract

Mukonal is an active member of carbazole alkaloids isolated from Murraya koenigii. It has been shown to possess remarkable biological and pharmacological activities including anticancer activity. Therefore, the aim of current investigation was to explore anti-breast cancer activity of mukonal and to explore the underlying mechanism. Results indicate that mukonal has potential to induce antiproliferative effects against MDA-MB-231 and SK-BR-3 cells with an IC 50 of 7.5 µM. No significant toxicity of mukonal was observed in case of normal breast cells. The antiproliferative effects of mukonal were found to proceed via apoptosis, which was further supported by increased cleavage of PARP and caspase-3 and reduced expression of Bcl-2. Mukonal induced autophagic cells death in breast cancer cells as was evidenced by formation of autophagosomes and enhanced expressions of Beclin-1, LC3B-I and LC3B-II proteins. In vivo examination of anti-breast cancer property of mukonal indicated that it could potentially reduce tumor weight and volume in xenografted mice models. In conclusion, mukonal has a remarkable potential of inhibiting breast cancer via induction of apoptosis and autophagy. Mukonal also inhibited xenografted tumors models in a dose-dependent manner. Therefore, mukonal may prove lead molecule in breast cancer drug discovery and treatment provided further investigations are recommended.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…and Pellina sp. p62/SQSTM1, LC3-II↑ Inhibit autophagy AsPC-1 and PANC-1 Pancreatic cancer [ 216 ] Indole-3-carbinol Cruciferous vegetables p62↓ LC3-II↑ Induce autophagy EAC cell Ehrlich ascites carcinoma [ 219 ] Mukonal Murraya koenigii Beclin-1↑ Induce autophagy MDA-MB-231; SK-BR-3 (IC 50 = 7.5 μM) Breast cancer [ 228 ] Evodiamine Evodia rutaecarpa Beclin-1↑ Induce autophagy SGC-7901 Gastric cancer [ 229 ] Bufothionine Toad Bufo bufo gargarizans Cantor JAK2/STAT3↓ Induce autophagy SMMC-7721 Hepatocellular carcinoma [ 233 ] Reduced scytonemin Nostoc commune ROS↑ LC3-II↑ Induce autophagy Jurkat (IC 50 = 1.8 μM) Leukemia [ 239 ] Fascaplysin Fascaplysinopsis sp. ROS, p8↑ …”

“…In mukonal-treated breast cancer cells, there was an increase in the expression level of autophagy proteins, Beclin-1, LC3-I, and LC3-II, thus leading to autophagic cell death. Besides, in vivo experiment indicated that mukonal could significantly reduce tumor weight and volume [ 228 ]. Moreover, Beclin-1 was also involved in the evodiamine-induced autophagic death of gastric cancer cells, and its expression level was significantly increased in SGC-7901 cells [ 229 ].…”

The anticancer activity of carbazole alkaloids

“…Mukonal (Figure 4 and Table 3; 20, IC 50 : 7.5 µM, MTT assay), an active member of carbazole alkaloids isolated from Murraya koenigii, had the potential to induce antiproliferative effects against MDA-MB-231 and SK-BR-3 cells and no significant toxicity (IC 50 : 110 µM) of mukonal was observed in case of normal MB-157 breast cells. [57,58] 7-Methoxymukonal (21, IC 50 : 82.6 µM, MTT assay), isolated from the root bark of Clausena harmandiana, showed moderate activity against HepG2 cells. [59] The mechanistic studies illustrated that cancer cells.…”

Cytotoxicity of Mahanimbine from Curry Leaves in Human Breast Cancer Cells (MCF-7) via Mitochondrial Apoptosis and Anti-Angiogenesis

“…Murraya species is one of the richest sources of carbazole alkaloids [25]. A few carbazole alkaloids such as mukonal, mahanine, and girinimbine isolated from this plant have shown significant anticancer activity, particularly in breast cancer [26][27][28][29]. Mahanimbine (MN) is a carbazole alkaloid and is present in the leaves of this plant (Figure 1A).…”