Curcumin induces apoptosis-independent death in oesophageal cancer cells

Abstract

BACKGROUND: Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines. METHODS: MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting. RESULTS: Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5 -50 mM range. Cytotoxicity is associated with accumulation in G2/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin -proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug. CONCLUSION: Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.

Involvement of ROS in Curcumin-induced Autophagic Cell Death

“…3D) further confirmed the involvement of ROS in autophagy. Our findings are consistent with previous reports which showed the non-apoptotic cell death of chronic myeloid leukemia cells and oesophageal cancer cells [30,32] in response to curcumin, although these authors did not claim the implication of ROS. In cervical cancer cells, curcumin was observed to mediate radiosensitization by increased ROS generation even at concentrations where curcumin itself had no effect on ROS production [33].…”

“…Autophagy which is designated as type II programmed cell death has also been reported to be an anticancer mechanism of curumin, resulting in the growth inhibition of a variety of malignant of cells such as chronic myeloid leukemia cells, malignant glioma cells, and oesophageal cancer cells [30][31][32]. We showed that curcumin induced autophagy in HCT116 human colon cancer cells, since curcumin caused the conversion of LC3 protein (Fig.…”

Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway

“…A link has been established between autophagic cell death and Bcl-2 anti-apoptotic proteins level of expression as it was reported that Bcl-xL binds and inhibits Beclin 1, an essential mediator of autophagy (36,37). Similarly, induction of specific features of apoptosis-independent cell death corresponding to autophagy was observed in oesophageal cancer cells after curcumin treatment (38). Autophagy was reported to be a back-up cell death mechanism when other cell deaths mechanisms failed and is now considered as a target for novel approaches in anticancer therapy (39).…”

Liposomal curcumin inhibits Lewis lung cancer growth primarily through inhibition of angiogenesis

“…Curcumin has been proven to be a promising anti-cancer drug by induction of apoptosis and apoptosis-independent death, and inhibition of proliferation and angiogenesis (1)(2)(3)(4). Phase I and II studies of this compound have shown that curcumin is well tolerated and is effective for cancer patients; however, its benefits may be attenuated due to its low bioavailability through oral administration for non-gastrointestinal cancers (5,6).…”