Thymoquinone induces apoptosis through activation of caspase‐8 and mitochondrial events in p53‐null myeloblastic leukemia HL‐60 cells

Abstract

Thymoquinone (TQ), the major biologically active component isolated from a traditional medicinal herb, Nigella sativa Linn, is a potential chemopreventive and chemotherapeutic compound. Despite the promising antineoplastic activities of TQ, the molecular mechanism of its pharmacologic effects is poorly understood. Here, we report that TQ exhibits antiproliferative effect, induces apoptosis, disrupts mitochondrial membrane potential and triggers the activation of caspases 8, 9 and 3 in myeloblastic leukemia HL-60 cells. The apoptosis induced by TQ was inhibited by a general caspase inhibitor, z-VAD-FMK; a caspase-3-specific inhibitor, z-DEVD-FMK; as well as a caspase-8-specific inhibitor, z-IETD-FMK. Moreover, the caspase-8 inhibitor blocked the TQ-induced activation of caspase-3, PARP cleavage and the release of cytochrome c from mitochondria into the cytoplasm. In addition, TQ treatment of HL-60 cells caused a marked increase in Bax/Bcl2 ratios due to upregulation of Bax and downregulation of Bcl2 proteins. These results indicate that TQ-induced apoptosis is associated with the activation of caspases 8, 9 and 3, with caspase-8 acting as an upstream activator. Activated caspase-8 initiates the release of cytochrome c during TQ-induced apoptosis. Overall, these results offer a potential mechanism for TQ-induced apoptosis in p53-null HL-60 cancer cells. ' 2005 Wiley-Liss, Inc.

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

“…Thymoquinone (TQ), the most abundant component of black seed oil, has been reported to exhibit antioxidant (4)(5)(6), antiinflammatory, and chemopreventive (7-9) effects. For instance, TQ has been shown to suppress the proliferation of various tumor cells, including colorectal carcinoma, breast adenocarcinoma, osteosarcoma, ovarian carcinoma, myeloblastic leukemia, and pancreatic carcinoma (7,(10)(11)(12)(13)(14), although it is minimally toxic to normal cells (15).…”

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

“…Cell proliferation (Fig. 1A) and cell viability ( A c c e p t e d M a n u s c r i p t respond to TQ within 24h and at the previously published concentrations [24][25][26][27][28].…”

“…It has been suggested that TQ, as a DNA damaging agent, is a potential reactive oxygen species (ROS) producer which exerts its anti-cancer effects by inhibiting cell growth, arresting cell cycle progression and inducing subsequently apoptosis [23][24][25][26][27][28][29]. p53-dependent [26] and p53-independent pathways [23,27] have been evidenced to explain the cellular actions of TQ. In HCT-116 colorectal cancer cells, TQ-induced apoptosis involves an upregulation of both p53 and p21 WAF1/CIP1 expressions, concomitantly with a downregulation of the expression of the anti-apoptotic protein Bcl-2 [26].…”

“…In HCT-116 colorectal cancer cells, TQ-induced apoptosis involves an upregulation of both p53 and p21 WAF1/CIP1 expressions, concomitantly with a downregulation of the expression of the anti-apoptotic protein Bcl-2 [26]. In p53-null myeloblastic leukemia HL-60 cells [27] and in p53-null osteosarcoma MG63 cells [28], the anti-cancer activities of TQ involve alterations of the Bax/Bcl2 ratio and caspase activations, but the precise mechanisms remain unknown.…”

Cytotoxicity of Nigella Sativa Seed Oil and Extract Against Human Lung Cancer Cell Line

“…cancer diseases, including cervical cancer (Effenberger et al, 2010), blood cancer (El-Mahdy et al, 2005), hepatic cancer (Thabrew et al, 2005), colon cancer (Salim and Fukushima, 2003), pancreatic cancer (Chehl et al, 2009), skin cancer (Salomi et al, 1991), fibrosarcoma (Awad, 2005), renal cancer (Khan and Sultana, 2005), prostate cancer (Yi et al, 2008), and breast cancers (Farah and Begum, 2003;Ahmad et al, 2012). Pharmacologically important components of N sativa extracts have also been studied against lung cancer as an anticancer agent.…”