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Cancer Therapy. (cancer + therapy)
Selected AbstractsA role for endogenous reverse transcriptase in tumorigenesis and as a target in differentiating cancer therapyGENES, CHROMOSOMES AND CANCER, Issue 1 2006Paola Sinibaldi-Vallebona An unexpected result emerging from completion of the genome sequencing project is that a large portion of mammalian genomes is constituted by retrotransposons. A large body of published data supports the conclusion that retrotransposons are biologically active elements and indicates that retrotransposition is an ongoing process in mammalian genomes. Retroelements can act as insertional mutagens altering the coding integrity of genes and, recently, have been found to also affect the expression of cellular genes at the epigenetic level: in this light, they are a potential threat in that these events can trigger the onset of several pathologies including cancer. Retroelement genes, and particularly the gene coding for reverse transcriptase (RT), are typically expressed at high levels in transformed cells and tumors. In recent work, we have found that drug-mediated inhibition of the endogenous RT activity, or silencing of expression of active retrotransposons of the LINE-1 family by RNA interference, down-regulate cell growth and induce the activation of differentiating functions in several cancer cell lines. Moreover, the inhibition of endogenous RT activity in vivo antagonizes the growth of human tumors in animal models. In this review, we discuss newly emerging concepts on the role of retrotransposons and suggest that an abnormally high level of the RT activity that they encode may contribute to the loss of control in the proliferation and differentiation programs typical of transformed cells. In this light, RT-coding elements may be regarded as promising targets in the development of novel, differentiation-inducing approaches to cancer therapy. © 2005 Wiley-Liss, Inc. [source] MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells,HEPATOLOGY, Issue 1 2009Teng Xu Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (HEPATOLOGY 2009.) [source] In vitro and in vivo evaluation and a case report of intense nanosecond pulsed electric field as a local therapy for human malignanciesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Edward B. Garon Abstract When delivered to cells, very short duration, high electric field pulses (nanoelectropulses) induce primarily intracellular events. We present evidence that this emerging modality may have a role as a local cancer therapy. Five hematologic and 16 solid tumor cell lines were pulsed in vitro. Hematologic cells proved particularly sensitive to nanoelectropulses, with more than a 60% decrease in viable cells measured by MTT assay 96 hr after pulsing in 4 of 5 cell lines. In solid tumor cell lines, 10 out of 16 cell lines had more than a 10% decrease in viable cells. AsPC-1, a pancreatic cancer cell line, demonstrated the greatest in vitro sensitivity among solid tumor cell lines, with a 64% decrease in viable cells. When nanoelectropulse therapy was applied to AsPC-1 tumors in athymic nude mice, responses were seen in 4 of 6 tumors, including clinical complete responses in 3 of 6 animals. A single human subject applied nanoelectropulse therapy to his own basal cell carcinoma and had a complete pathologic response. In summary, we demonstrate that electric pulses 20 ns or less kill a wide variety of human cancer cells in vitro, induce tumor regression in vivo, and show efficacy in a single human patient. Therefore, nanoelectropulse therapy deserves further study as a potentially effective cancer therapy. © 2007 Wiley-Liss, Inc. [source] Core/shell pH-sensitive micelles self-assembled from cholesterol conjugated oligopeptides for anticancer drug deliveryAICHE JOURNAL, Issue 7 2010Xin Dong Guo Abstract A doxorubicin (DOX) delivery system of pH-sensitive micelles self-assembled from cholesterol conjugated His5Arg10 (HR15-Chol) and His10Arg10 (HR20-Chol) has been described in this article. The amphiphilic molecules have low critical micelle concentrations of 17.8 and 28.2 ,g/mL for HR15-Chol and HR20-Chol, respectively, even at a low pH of 5.0. The pH-sensitive histidine segment of the polypeptide block is insoluble at pH 7.4 but becomes positively charged and soluble via protonation at pH lower than 6.0. The size and zeta potential of DOX-loaded micelles increases with the decrease in pH. Coarse-grained simulations were performed to verify the structure of DOX-loaded micelles and pH sensitivity of HR15/20-Chol. The in vitro DOX release from the micelles is significantly accelerated by decreasing pH from 7.4 to 5.0. Furthermore, DOX release from the micelles is controlled by a Fickian diffusion mechanism. These micelles have great potential applications in delivering hydrophobic anticancer drugs for improved cancer therapy. © 2009 American Institute of Chemical Engineers AIChE J, 2010 [source] Antiangiogenic drugs: Current knowledge and new approaches to cancer therapyJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2008Jose L. Mauriz Abstract Angiogenesis,process of new blood-vessel growth from existing vasculature,is an integral part of both normal developmental processes and numerous pathologies such as cancer, ischemic diseases and chronic inflammation. Angiogenesis plays a crucial role facilitating tumour growth and the metastatic process, and it is the result of a dynamic balance between proangiogenic and antiangiogenic factors. The potential to block tumour growth and metastases by angiogenesis inhibition represents an intriguing approach to the cancer treatment. Angiogenesis continues to be a topic of major scientific interest; and there are currently more antiangiogenic drugs in cancer clinical trials than those that fit into any other mechanistic category. Based on preclinical studies, researchers believe that targeting the blood vessels which support tumour growth could help treatment of a broad range of cancers. Angiogenic factors or their receptors, endothelial cell proliferation, matrix metalloproteinases or endothelial cell adhesion, are the main targets of an increasing number of clinical trials approved to test the tolerance and therapeutic efficacy of antiangiogenic agents. Unfortunately, contrary to initial expectations, it has been described that antiangiogenic treatment can cause different toxicities in cancer patients. The purpose of this article is to provide an overview of current attempts to inhibit tumour angiogenesis for cancer therapy. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4129,4154, 2008 [source] Self-immolative dendrimers as novel drug delivery platformsJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 5 2006Doron Shabat Abstract Self-immolative dendrimers were recently developed and introduced as a potential platform for a single-triggered multi-prodrug. These unique structural dendrimers can release all of their tail units through domino-like chain fragmentation, which is initiated by a single cleavage at the dendrimer core. The incorporation of drug molecules as the tail units and an enzyme substrate as the trigger generates a multi-prodrug unit that is activated with a single enzymatic cleavage. We have demonstrated several examples of self-immolative dendritic prodrug systems and have shown significant advantages with respect to the appropriate monomeric prodrug. We anticipate that single-triggered, dendritic prodrugs will be exploited to further improve selective chemotherapeutic approaches in cancer therapy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1569,1578, 2006 [source] Cisplatin resistance conferred by the RAD51D (E233G) genetic variant is dependent upon p53 status in human breast carcinoma cell linesMOLECULAR CARCINOGENESIS, Issue 7 2009Aditi Nadkarni Abstract RAD51D, a paralog of the mammalian RAD51 gene, contributes towards maintaining genomic integrity by homologous recombination DNA repair and telomere maintenance. A RAD51D variant, E233G, was initially identified as a potential susceptibility allele in high-risk, site-specific, familial breast cancer. We describe in this report that the Rad51d (E233G) genetic variant confers increased cisplatin resistance and cell growth phenotypes in human breast carcinoma cell lines with a mutant p53 gene (BT20 and T47D) but not with a wild-type p53 gene (MCF-7). Treatment with a p53 specific inhibitor, pifithrin ,, restored this resistant phenotype in the MCF-7 cell line. Additionally, Rad51d (E233G) conferred increased cisplatin resistance of an MCF7 cell line in which p53 expression was stably knocked down by shRNAp53, indicating that the effect of this variant is dependent upon p53 status. Further study of Rad51d (E233G) will provide mechanistic insight towards the role of RAD51D in cellular response to anticancer agents and as a potential target for cancer therapy. © 2009 Wiley-Liss, Inc. [source] Polyporenic acid C induces caspase-8-mediated apoptosis in human lung cancer A549 cellsMOLECULAR CARCINOGENESIS, Issue 6 2009Hui Ling Abstract Lung cancer continues to be the leading cause of cancer-related mortality worldwide. This warrants the search for new and effective agents against lung cancer. We and others have recently shown that lanostane-type triterpenoids isolated from the fungal species Poria cocos (P. cocos) can inhibit cancer growth. However, the mechanisms responsible for the anticancer effects of these triterpenoids remain unclear. In this study, we investigated the effect of polyporenic acid C (PPAC), a lanostane-type triterpenoid from P. cocos, on the growth of A549 nonsmall cell lung cancer cells (NSCLC). The results demonstrate that PPAC significantly reduced cell proliferation via induction of apoptosis as evidenced by sub-G1 analysis, annexin V-FITC staining, and increase in cleavage of procaspase-8, -3, and poly(ADP-ribose)-polymerase (PARP). However, unlike our previously reported lanostane-type triterpenoid, pachymic acid, treatment of cells with PPAC was not accompanied by disruption of mitochondrial membrane potential and increase in cleavage of procaspase-9. Further, PPC-induced apoptosis was inhibited by caspase-8 and pan caspase inhibitors but not by a caspase-9 inhibitor. Taken together, the results suggest that PPAC induces apoptosis through the death receptor-mediated apoptotic pathway where the activation of caspase-8 leads to the direct cleavage of execution caspases without the involvement of the mitochondria. Furthermore, suppressed PI3-kinase/Akt signal pathway and enhanced p53 activation after PPAC treatment suggests this to be an additional mechanism for apoptosis induction. Together, these results encourage further studies of PPAC as a promising candidate for lung cancer therapy. © 2008 Wiley-Liss, Inc. [source] Activation of ASC induces apoptosis or necrosis, depending on the cell type, and causes tumor eradicationCANCER SCIENCE, Issue 8 2010Kou Motani The adaptor protein ASC (also called TMS1) links certain NLR proteins (e.g., NLRC4, NLRP3) and caspases. It is involved in the chemosensitivity of tumor cells and inflammation. Here, we found that ASC activation using NLRC4 mimicry or an autoinflammatory disease-associated NLRP3 mutant induced necrosis in COLO205 colon adenocarcinoma cells, but induced caspase-8-dependent apoptosis in NUGC-4 stomach cancer cells. As the Fas ligand induced caspase-8-dependent apoptosis in COLO205 cells, caspase-8 was intact in this cell line. ASC-mediated necrosis was preceded by lysosomal leakage, and diminished by inhibitors for vacuolar H+ -ATPase, cathepsins, and calpains but not by inhibitors for caspase-8, or aspartic proteases, suggesting that lysosomes and certain proteases were involved in this process. Finally, growing tumors of transplanted human cancer cells in nude mice were eradicated by the activation of endogenous ASC in the tumor cells, irrespective of the form of cell death. Thus, ASC mediates distinct forms of cell death in different cell types, and is a promising target for cancer therapy. (Cancer Sci 2010) [source] Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cellsCANCER SCIENCE, Issue 10 2009Noritaka Ohga The polyphenol epigallocatechin-3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the anti-angiogenic effect of EGCG on tumor-associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor-induced mobilization of EPC into circulation was inhibited by EGCG. MMP-9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP-9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective anti-angiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. (Cancer Sci 2009; 100: 1963,1970) [source] Clinical relevance of the homologous recombination machinery in cancer therapyCANCER SCIENCE, Issue 2 2008Kiyoshi Miyagawa Cancer chemotherapy and radiotherapy kill cancer cells by inducing DNA damage, unless the lesions are repaired by intrinsic repair pathways. DNA double-strand breaks (DSB) are the most deleterious type of damage caused by cancer therapy. Homologous recombination (HR) is one of the major repair pathways for DSB and is thus a potential target of cancer therapy. Cells with a defect in HR have been shown to be sensitive to a variety of DNA-damaging agents, particularly interstrand crosslink (ICL)-inducing agents such as mitomycin C and cisplatin. These findings have recently been applied to clinical studies of cancer therapy. ERCC1, a structure-specific endonuclease involved in nucleotide excision repair (NER) and HR, confers resistance to cisplatin. Patients with ERCC1-negative non-small-cell lung cancer were shown to benefit from adjuvant cisplatin-based chemotherapy. Imatinib, an inhibitor of the c-Abl kinase, has been investigated as a sensitizer in DNA-damaging therapy, because c-Abl activates Rad51, which plays a key role in HR. Furthermore, proteins involved in HR have been shown to repair DNA damage induced by a variety of other chemotherapeutic agents, including camptothecin and gemcitabine. These findings highlight the importance of HR machinery in cancer therapy. (Cancer Sci 2008; 99: 187,194) [source] Photodynamic therapy-generated tumor cell lysates with CpG-oligodeoxynucleotide enhance immunotherapy efficacy in human papillomavirus 16 (E6/E7) immortalized tumor cellsCANCER SCIENCE, Issue 5 2007Su-Mi Bae Immunotherapy with photodynamic therapy (PDT) offers great promise as a new alternative for cancer treatment; however, its use remains experimental. In this study, we examined the immunotherapeutic significance of human papillomavirus (HPV)-immortalized tumor cell lysates induced by PDT with CpG-oligodeoxynucleotide (ODN). PDT-cell lysates were generated by irradiating Radachlorin (5 µg/mL) preloaded TC-1 cells carrying HPV 16 E7. PDT-cell lysates plus ODN coinjection for protection against E7-expressing tumors as well as specific immune responses were evaluated with the following tests: heat shock protein 70 (HSP70) enzyme-linked immunosorbent assay, in vitro and in vivo tumor growth inhibition, interferon-, (IFN-,) and tumor necrosis factor-, (TNF-,) assay, cytotoxic T-lymphocyte assay, and fluorescence activated cell sorting (FACS) analysis. PDT-cell lysates plus ODN coinjection showed a significant suppression of tumor growth at both prophylactic and therapeutic levels, compared to PDT (or F/T)-cell lysates or ODN alone. In addition, we evaluated the level of the immune response with the coinjection. HSP70, an important regulator of inflammatory and immune response, was observed in abundance in the PDT-cell lysates. IFN-, production and cytotoxic T lymphocytes (CTL) responses were induced by PDT-cell lysates plus ODN injection. The coinjection resulted in PDT-cell lysate-specific antibodies (IgG1, IgG2a, IgG2b, and IgG3) and T-helper cell responses significantly higher than PDT-cell lysates alone. Moreover, IFN-, production and CTL responses were significantly induced in the PDT-cell lysate plus ODN immunized groups. These enhanced immune responses appeared to be mediated by CD8+ T cells only. These data suggest that PDT-cell lysates plus ODN injection may be an effective approach to induce CTL immune responses as a possible immunotherapeutic strategy for cancer therapy. (Cancer Sci 2007; 98: 747,752) [source] Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivoCANCER SCIENCE, Issue 7 2006Seiji Hosaka We previously reported that heat shock protein 105 (HSP105), identified by serological analysis of a recombinant cDNA expression library (SEREX) using serum from a pancreatic cancer patient, was overexpressed in various human tumors and in the testis of adult men by immunohistochemical analysis. In the present study, to elucidate the biological function of the HSP105 protein in cancer cells, we first established NIH3T3 cells overexpressing murine HSP105 (NIH3T3-HSP105). The NIH3T3-HSP105 cells acquired resistance to apoptosis induced by heat shock or doxorubicin. The small interfering RNA (siRNA)-mediated suppression of HSP105 protein expression induced apoptosis in human cancer cells but not in fibroblasts. By a combination of siRNA introduction and doxorubicin or heat shock treatment, apoptosis was induced synergistically in a human colon cancer cell line, HCT116. In vivo, siRNA inoculation into the human gastric cancer cell line KATO-3 established in the flank of an NOD SCID mouse suppressed the tumor growth. This siRNA-induced apoptosis was mediated through caspases, but not the p53 tumor suppressor protein, even though the HSP105 protein was bound to wild-type p53 protein in HCT116 cells. These findings suggest that the constitutive overexpression of HSP105 in cancer cells is involved in malignant transformation by protecting tumor cells from apoptosis. HSP105 may thus be a novel target molecule for cancer therapy and a treatment regimen using synthetic siRNA to suppress the expression of HSP105 protein may provide a new strategy for cancer therapy. (Cancer Sci 2006; 97: 623,632) [source] | |||||||||||||