BackgroundNumerous studies have demonstrated that autophagy plays a vital role in maintaining cellular homeostasis. Interestingly, several anticancer agents were found to exert their anticancer effects by triggering autophagy. Emerging data suggest that autophagy represents a novel mechanism that can be exploited for therapeutic benefit. Pharmacologically active natural compounds such as those from marine, terrestrial plants and animals represent a promising resource for novel anticancer drugs. There are several prominent examples from the past proving the success of natural products and derivatives exhibiting anticancer activity. Helenalin, a sesquiterpene lactone has been demonstrated to have potent anti-inflammatory and antitumor activity. Albeit previous studies demonstrating helenalin’s multi modal action on cellular proliferative and apoptosis, the mechanisms underlying its action are largely unexplained.MethodsTo deduce the mechanistic action of helenalin, cancer cells were treated with the drug at various concentrations and time intervals. Using western blot, FACS analysis, overexpression and knockdown studies, cellular signaling pathways were interrogated focusing on apoptosis and autophagy markers.ResultsWe show here that helenalin induces sub-G1 arrest, apoptosis, caspase cleavage and increases the levels of the autophagic markers. Suppression of caspase cleavage by the pan caspase inhibitor, Z-VAD-fmk, suppressed induction of LC3-B and Atg12 and reduced autophagic cell death, indicating caspase activity was essential for autophagic cell death induced by helenalin. Additionally, helenalin suppressed NF-κB p65 expression in a dose and time dependent manner. Exogenous overexpression of p65 was accompanied by reduced levels of cell death whereas siRNA mediated suppression led to augmented levels of caspase cleavage, autophagic cell death markers and increased cell death.ConclusionsTaken together, these results show that helenalin mediated autophagic cell death entails inhibition of NF-κB p65, thus providing a promising approach for the treatment of cancers with aberrant activation of the NF-κB pathway.
An essential oil extract, derived from the rhizome of Curcuma wenyujin (CWE), possesses antioxidative, antimicrobial, and anti-inflammatory properties. However, it remains unknown how exactly CWE inhibits tumor growth. In this study, using human cervical cancer HeLa cells, the authors postulated that CWE has the ability to inhibit tumor growth. The study shows that CWE dose-dependently suppressed colony formation and inhibited the proliferation of HeLa cells through blockade of cell cycle progression at G1 phase and apoptosis. CWE-induced G1 arrest was associated with retinoblastoma protein dephosphorylation and reduced amounts of cyclins D1 and D3, and cyclin-dependent kinase 4 and 6 proteins. CWE treatment resulted in apoptosis in HeLa cells as evidenced by morphological changes, caspase activation and PARP cleavage, which can be reversed by a pan-caspase inhibitor. It was observed that CWE treatment activated the mitochondrial apoptotic pathway indicated by a decrease in Mcl-1 and Bcl-xL levels, resulting in mitochondrial membrane potential loss and caspases 9 activation. CWE-treated cells displayed reduced PTEN, AKT, and STAT3 phosphorylation and downregulation of NFkB signaling, providing a mechanism for the G1 arrest and apoptosis observed. Furthermore, CWE inhibited tumor growth of HeLa in a xenograft mouse tumor model, suggesting that CWE inhibited tumorigenesis by inhibiting cell proliferation and inducing apoptosis. These findings are the first to reveal the molecular basis for the anticervical cancer action of CWE. The results suggest that CWE could be developed as a drug for the management of cervical cancer.
Kruppel-like factor 4 (KLF4) belongs to a family of evolutionarily conserved zinc finger-containing transcription factors. It has been shown to mediate self renewal and pluripotency, regulate adipogenesis and play a critical role in monocyte differentiation. KLF4 is also highly expressed in squamous cell carcinomas and in 70% of all primary human breast cancers, suggesting a putative role for KLF4 as being an oncogene and as an antiapoptotic factor. However, the mechanism of this regulation remains unclear. Here, we show that KLF4 is induced during histone deacetylase inhibitor treatment, and regulates the extrinsic apoptosis pathway by inhibiting caspase cleavage. In addition, KLF4 binds to the p57(Kip2) promoter and transcriptionally upregulates its expression, which in turn inhibits the stress activated protein kinase cascade and c-Jun phosphorylation. Our findings indicate that in cancer cells that express high levels of KLF4 may be refractory to HDACi treatment. Results of our study demonstrate an unexpected antiapoptotic function of KLF4, and suggest an important cell fate determinant following histone deacetylase inhibitor induced apoptosis.
Chemoresistance to anticancer drugs is a common and troublesome occurrence in ovarian cancer patients. Despite advances in surgical and chemotherapeutic modalities, survival rates remain alarmingly low. Hence, it has been suggested that strategies for reversing multidrug resistance (MDR) are top priorities for reducing cancer mortality. Thapsigargin (TG), a sesquiterpene lactone isolated from the roots of Thapsia garganica, has been demonstrated to possess anticancer properties. The impact of TG, however, on chemoresistance has not been fully elucidated. Here, we report the effects of combining TG with doxorubicin (DOX), since DOX forms part of the standard treatment for women with advanced ovarian cancer. Multidrug-resistant A2780/MDR human ovarian carcinoma cells were treated with TG in combination with a clinically relevant concentration of DOX (10 µM) and assessed for cell proliferation using the MTT assay. A2780/MDR cells were 100-fold more resistant to DOX than parental A2780 cells on the basis of MTT assay. The IC50 of DOX decreased from 8.02 µM to 0.07 µM, in the presence of 1 µMTG, after 24 h of continuous drug combination exposure, producing a 115-fold reversal of MDR. Flow cytometric analysis of cells treated for 24 h with 10 µM DOX with and without 5 µMTG demonstrated significantly increased apoptosis in the presence of TG. TG by itself had little effect on the viability of A2780/MDR cells, as evident by less than 5% cell death after 24-h TG treatment. The activation of caspases-3 and -9 and PARP cleavage were enhanced in combination therapy relative to single agent treatments. Combined treatment with TG and DOX also increased JNK phosphorylation in A2780/MDR cells and pretreatment with JNK inhibitor SP600125 partially rescued apoptosis. Our data demonstrated that addition of TG at subtoxic concentration restored the sensitivity to DOX-induced apoptosis in A2780/MDR cells via JNK pathway. Taken together, these data support the concurrent use of DOX and TG in ovarian cancer therapeutics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B67.
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