Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl

Abstract

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…One of the more extensively studied compounds in this group is curcumin, a diferuloylmethane derived from turmeric, which has been shown to suppress NF-kB activation and NF-kB-dependent gene expression. Previous studies had indicated that curcumin has strong antitumor effects on AML and prostate cancer cell lines (Mukhopadhyay et al, 2001;Anto et al, 2002). Recently, curcumin has been shown to induce growth arrest and apoptosis in mantle cell lymphoma cell lines (Shishodia et al, 2005), where it suppressed the expression of the genes encoding cyclin D1, Bcl-2 and Bcl-xL, all known NF-kB target genes.…”

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

“…Curcumin is one of the most potent activators of apoptosis in tumor cells [16]. We investigated whether GSH can modulate curcumin's ability to induce apoptosis.…”

“…This phytochemical has also been shown to suppress the proliferation of a wide variety of tumor cells by downregulating c-myc [6], cyclin D1 [12], activator protein-1 (AP-1) [13], phosphatidylinositol-3-kinase/AKT signaling [14], and epidermal growth factor receptor (EGFR) signaling [15]. Curcumin can also induce apoptosis through the modulation of antiapoptotic gene products [2,6] and BID cleavage, cytochrome c release, and caspase-9 activation, leading to caspase-3 activation [16]. More recently, curcumin was found to bind to thioredoxin reductase and alkylate a critical cysteine residue, thus converting the activity of the enzyme to NADPH oxidase [17].…”

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

“…4A, upper panel) and the proapoptotic protein Bax in a time-dependent manner. Because chemotherapeutic agents induce apoptosis through the caspase-8-mediated cleavage of Bid, a proapoptotic member of the bcl-2 family [34], we investigated guggulsterone's effect on Bid cleavage. Western blot analysis demonstrated that guggulsterone also induced Bid cleavage in a time-dependent manner (Fig.…”