Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

Abstract

Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients’ survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a “multifunctional drug”. We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species’intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR.

Curcumin: A naturally occurring autophagy modulator

“…Yamauchi et al () employing ACC‐MESO‐1 as a human‐derived mesothelioma cell line, observed that curcumin decreased cell viability and gave rise to autophagy through the increased LC3B‐II expression and autophagosome formation, but not apoptosis. On the other hand, Masuelli et al () recently observed that curcumin activated apoptosis in a range of human (MM‐B1, H‐Meso‐1, and MM‐F1) and mouse (#40a) malignant mesothelioma cell lines, while elevating Bax/Bcl‐2 ratio, p53 expression, caspase 9 activation, ERK1/2 and p38 phosphorylation, c‐Jun expression and phosphorylation, poly(ADP‐ribose)polymerase 1 cleavage, and yet declining nuclear factor‐κB nuclear translocation, p54 JNK, and Akt phosphorylation. Interestingly, curcumin also evoked and subsequently abolished autophagy as presented by changes in p62 expression in this setting.…”

Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer

“…Several studies have demonstrated that curcumin is capable of inducing autophagy in different lines of human tumor and normal cells [22,23,[27][28][29]. However, recent studies have revealed that curcumin impairs autophagic flux both in vitro and in vivo [30,31]. The roles of curcumin and its analogs on autophagy regulation remain controversial because in most studies, especially in the earlier studies, the autophagic flux was not carefully examined.…”

Autophagy-Inducing Effect of Compound Berberine on CNE2 NPC Cells via Interference with the Targets in P13K/AKT/mTOR Signaling Pathway

“…Based on the discussion above, we could deduce that one of the important mechanisms for CBBR to inhibit the proliferating activity of CNE2 cells might be achieved through activating their autophagic response, as that of quercetin to promote hepatoma cells going into apoptotic program via inducing autophagy at first [29]. Meanwhile, curcumin could induce apoptosis in malignant mesothelioma cells through initiating autophagy flow so as to suppress their level of proliferation [30]. Some ingredients of herbal medicine, such as TanshinoneI (TSI) and…”