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1.  Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch 
Cancer cells have developed novel mechanisms for evading chemotherapy-induced apoptosis and autophagy-associated cell death pathways. Upon the discovery that chemotherapeutics could target these cell death pathways in a manner that was not mutually exclusive, new discoveries about the interrelationship between these two pathways are emerging. Key proteins originally thought to be “autophagy-related proteins” are now found to be involved in either inducing or inhibiting apoptosis. Similarly, apoptosis inhibiting proteins can also block autophagy-associated cell death. One example is the complex formed by the autophagy protein, Beclin 1, and anti-apoptotic protein Bcl-2, which leads to inhibition of autophagy-associated cell death. Researchers have been investigating additional mechanisms that form/disrupt this complex in order to better design chemotherapeutics. This review will highlight the role Bcl-2 and Beclin 1 play in cancer development and drug resistance, as well as the role the Bcl-2:Beclin 1 complex in the switch between autophagy and apoptosis.
PMCID: PMC3304572  PMID: 22485198
Apoptosis; autophagy; Bcl-2; Beclin 1; Gossypol; BH3 mimetics
2.  Tumor-targeted RNA-interference: functional non-viral nanovectors 
While small interfering RNA (siRNA) and microRNA (miRNA) have attracted extensive attention and showed significant promise for the study, diagnosis and treatment of human cancers, delivering siRNA or miRNA specifically and efficiently into tumor cells in vivo remains a great challenge. Delivery barriers, which arise mainly from the routes of administration associated with complex physiochemical microenvironments of the human body and the unique properties of RNAs, hinder the development of RNA-interference (RNAi)-based therapeutics in clinical practice. However, in available delivery systems, non-viral nanoparticle-based gene/RNA-delivery vectors, or nanovectors, are showing powerful delivery capacities and huge potential for improvements in functional nanomaterials, including novel fabrication approaches which would greatly enhance delivery performance. In this review, we summarize the currently recognized RNAi delivery barriers and the anti-barrier requirements related to vectors’ properties. Recent efforts and achievements in the development of novel nanomaterials, nanovectors fabrication methods, and delivery approaches are discussed. We also review the outstanding needs in the areas of material synthesis and assembly, multifunction combinations, proper delivery and assisting approaches that require more intensive investigation for the comprehensive and effective delivery of RNAi by non-viral nanovectors.
PMCID: PMC3092671  PMID: 21572539
Nanoparticles; RNAi; siRNA; miRNA; cancer therapy; tumor-targeting
3.  Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer 
Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.
PMCID: PMC3144474  PMID: 21804946
IAP inhibitor; Embelin; prostate cancer; ionizing radiation therapy
4.  Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer 
Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.
PMCID: PMC3144474  PMID: 21804946
IAP inhibitor; Embelin; prostate cancer; ionizing radiation therapy
5.  Tumor-targeted RNA-interference: functional non-viral nanovectors 
While small interfering RNA (siRNA) and microRNA (miRNA) have attracted extensive attention and showed significant promise for the study, diagnosis and treatment of human cancers, delivering siRNA or miRNA specifically and efficiently into tumor cells in vivo remains a great challenge. Delivery barriers, which arise mainly from the routes of administration associated with complex physiochemical microenvironments of the human body and the unique properties of RNAs, hinder the development of RNA-interference (RNAi)-based therapeutics in clinical practice. However, in available delivery systems, non-viral nanoparticle-based gene/RNA-delivery vectors, or nanovectors, are showing powerful delivery capacities and huge potential for improvements in functional nanomaterials, including novel fabrication approaches which would greatly enhance delivery performance. In this review, we summarize the currently recognized RNAi delivery barriers and the anti-barrier requirements related to vectors' properties. Recent efforts and achievements in the development of novel nanomaterials, nanovectors fabrication methods, and delivery approaches are discussed. We also review the outstanding needs in the areas of material synthesis and assembly, multifunction combinations, proper delivery and assisting approaches that require more intensive investigation for the comprehensive and effective delivery of RNAi by non-viral nanovectors.
PMCID: PMC3092671  PMID: 21572539
Nanoparticles; RNAi; siRNA; miRNA; cancer therapy; tumor-targeting

Results 1-5 (5)