Novel anti-cancer agent myrtucommulone-A and thymoquinone abrogate epithelial–mesenchymal transition in cancer cells mainly through the inhibition of PI3K/AKT signalling axis

Abstract

Epithelial-mesenchymal transition (EMT) plays a prominent role in cancer progression and metastasis. Inhibition of EMT-associated regulators may hold a huge promise for cancer therapy. Although TGF-β signalling has a pivotal role in the induction of EMT, alterations during the EMT process are usually initiated and controlled by the cross-talk of multiple signalling pathways, and in most cases this is context-dependent. In the present study, we aimed at identifying the molecular mechanisms during the inhibition of EMT by novel anti-cancer agent myrtucommulone-A (MC-A) and thymoquinone (TQ). We used epithelial cancer cells to study the effects of MC-A and TQ on EMT. We first showed the functional inhibition of EMT by MC-A or TQ using migration assays and confirmed the EMT inhibition by analysing the expression of EMT markers with RT-PCR, immunocytochemistry and Western blotting. We evaluated the changes in intracellular dynamics by Western blotting and compared the effects of MC-A and TQ with the effects of selective inhibitors of PI3K (LY294002), ERK 1/2 (U0126) and TGF-βR (SB431542). We demonstrate that both MC-A and TQ treatment negatively regulate the EMT process through modulation of signalling pathways in cancer cells. MC-A and TQ treatment inhibited phosphorylation of multiple proteins in a context-dependent manner. Novel anti-cancer agent MC-A and TQ regulate distinct signalling pathways for the repression of EMT which emphasises the significance of combinational therapies in cancer treatment. MC-A and TQ could be considered as candidate molecules for combinational therapies with their ability to interfere signalling pathways regulating cancer cell behaviour.

Cancer stem cells and epithelial–mesenchymal transition in urothelial carcinoma: Possible pathways and potential therapeutic approaches

“…NANOG, OCT4, SOX‐2, CD44) . Furthermore, they confirmed the functional inhibition of the EMT by MC‐A (thymoquinone was simultaneously analyzed) by testing the expression of EMT markers, and changes were found in the expression of proteins involved in the PI3K/AKT pathway; MC‐A and thymoquinone treatment inhibited the phosphorylation of those proteins in a context‐dependent manner . Although more research is required to identify the specific mechanisms, the current results support the possible therapeutic effect of targeting the PI3K/AKT pathway to inhibit the proliferation and metastasis of UCSCs.…”

Thymoquinone attenuates phosphorylation of AKT to inhibit kidney cancer cell proliferation

“…Recent reports suggest Tq to be effective in adjuvant cancer therapies (Mostofa, Hossain, Basak, & Sayeed, 2017). The effect of Tq has been proven against a variety of cancer types which include the cancer of bladder (Iskender, Izgi, & Canatan, 2016), breast (Dastjerdi, Mehdiabady, Iranpour, & Bahramian, 2016), colon (Chen et al, 2015) lung (Yang, Kuang, Lv, & Yan, 2015), and prostate (Richards, Jones, Hughes, Benghuzzi, & Tucci, 2006). However, the effect of this phytochemical on renal carcinoma cells and its mechanistic investigations need further research.…”

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects

“…TQ (2-isopropyl-5-methyl-1,4-benzoquinone), the main active component of the essential oil of Nigella sativa seeds, has various pharmacological effects. It has been reported to display various pharmacological activities such as antioxidant (7), antidiabetic (8), cardioprotective (9), hepatoprotective (10), neuroprotective (11), nephroprotective (12), anti-infl ammatory (13), anti-mutagenic (14), and anticancer (15) effects. TQ is of low toxicity (LD50 2.4 g/kg) and is well tolerated when given subchronically till 90 mg/ kg/day for 90 days (16).…”