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ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite progress in identifying "hallmark" genetic alterations associated with the main subtypes of epithelial ovarian cancer, the survival rate of women with EOC changed little since platinum-based treatment was introduced more than 30years ago. The successful identification of new, effective anticancer drugs largely depends on appropriate preclinical experimental models that should ideally mimic the complexity of different cancer forms. This review examines the preclinical ovarian cancer models available for a better understanding of the biological mechanisms of the development, progression, invasion and metastasis of EOC. We provide evidence that the preclinical models have been instrumental for a better understanding of the pathological events at the basis of ovarian carcinoma. The genetically engineered mouse (GEM) models of ovarian cancer have overcome some of the weaknesses of the xenograft models, such as the fact that these tumors arise orthotopically in immunologically intact mice and more closely resemble the behavior of human cancers. We envisage that in the near future these GEM models will play a key role in pre-selecting drug regimens with the greatest promise of efficacy in human clinical trials, making it easier and certainly less expensive to test new, different drug combinations.
Cancer treatment reviews 02/2013; · 5.30 Impact Factor
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Journal of Clinical Oncology 01/2013; · 18.37 Impact Factor
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ABSTRACT: The prognostic/predictive role of both CD133 and Aldehyde dehydrogenase (ALDH) expression in human ovarian cancer remains elusive. This is an observational study that investigated the expression of CD133 and of ALDH enzymatic activity in fresh ovarian cancer samples and their association with different clinic-pathological patient' characteristics and explored their possible predictive/prognostic role. We analyzed the expression of CD133 and ALDH enzymatic activity in 108 human ovarian cancer samples. We found that among the total patients analyzed, 13% of them was completely negative for ALDH activity and 26% was negative for CD133 staining. Both markers were variably expressed within the samples and when both studied in the same tumor sample, no statistically significant correlation between ALDH enzymatic activity and CD133 expression was found. No statistical significant correlation was found also between the percentage values of positive ALDH and CD133 cells and the number of serial passages patient's cultures underwent, suggesting that these markers do not confer by themselves a self-renewal growth advantage to the cultures. Lower levels of CD133 were associated with higher tumor grade. No correlation with response to therapy, progression free survival and overall survival was found. Our data suggest that neither ALDH enzymatic activity nor CD133 expression provide additional predictive/prognostic information in ovarian cancer patients.
American journal of cancer research. 01/2013; 3(2):221-229.
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ABSTRACT: Tivantinib is a selective, oral, non-ATP-competitive, small molecule inhibitor of the c-Met receptor, tyrosine kinase, which is implicated at different levels of tumor cell migration, invasion, proliferation, and metastasis. Tivantinib has shown antitumor activity in various human tumor cell lines and in xenograft models of human cancers, including non-small-cell lung cancer. Few therapeutic options are available at present for advanced non-small-cell lung cancer, so there is a pressing need for new therapeutic strategies to improve response and survival. Amplification of Met has been reported in more than 20% of lung tumors that have acquired resistance to epidermal growth factor receptor inhibitors, implying that treatment of these tumors with a c-Met inhibitor should overcome resistance. Tivantinib has shown interesting and promising results in advanced non-small-cell lung cancer and appears to be well tolerated, either alone or in combination with other drugs. An interesting additional feature is the ability of the drug to delay development of new metastasis, in agreement with the proposed role of Met in this particular setting.
Cancer Management and Research 01/2013; 5:15-20.
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ABSTRACT: Targeting Chk1 protein kinase can enhance the antitumor effects of radio- and chemotherapy. Recent evidence disclosed a role of Chk1 in unperturbed cell proliferation and survival, implying that Chk1 inhibitors could also be effective as single agents in tumors with a specific genetic background. To identify genes in synthetic lethality with Chk1, we did a high-throughput screening using a siRNA library directed against 719 human protein kinases in the human ovarian cancer cell line OVCAR-5, resistant to Chk1 inhibitors. Wee1 tyrosine kinase was the most significant gene in synthetic lethality with Chk1. Treatment with non-toxic concentrations of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) confirmed the marked synergistic effect in various human cancer cell lines (breast, ovarian, colon, prostate), independently of the p53 status. Detailed molecular analysis showed that the combination caused cancer cells to undergo premature mitosis before the end of DNA replication, with damaged DNA leading to cell death partly by apoptosis. In vivo treatment of mice bearing OVCAR-5 xenografts with the combination of Chk1 and Wee1 inhibitors led to greater tumor growth inhibition than with the inhibitors used as single agents with no toxicity. These data provide a strong rationale for the clinical investigation of the combination of a Chk1 and a Wee1 inhibitor.
Cell cycle (Georgetown, Tex.) 07/2012; 11(13):2507-17. · 5.36 Impact Factor
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Francesca Ricci,
Sergio Bernasconi,
Patrizia Perego,
Monica Ganzinelli,
Giorgio Russo,
Francesca Bono,
Costantino Mangioni,
Robert Fruscio,
Mario Signorelli, Massimo Broggini,
Giovanna Damia
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ABSTRACT: Solid tumors appear to contain a subpopulation of cells (tumor-initiating cells, TICs) that not only drives and sustains tumor growth, but is possibly responsible for recurrence. We isolated, after enzymatic digestion of primary ovarian carcinoma samples, a subpopulation of cells propagating as non-adherent spheres in medium suitable for tumor stem cells. These cells were able to self-renew in vitro, as suggested by PKH-26 staining studies, were tumorigenic and acquired an epithelial morphology when grown in FBS-supplemented medium, losing their tumorigenic potential. Interestingly, the tumorigenic potential of PKH-26 (high) - and PKH-26 (neg) -sorted cells was similar. These TIC-enriched cultures showed higher levels of genes involved in stemness than differentiated cells derived from them and were more resistant to the cytotoxic effects of some drugs but equally sensitive to others. The higher level of ABCG2 efflux pump could explain increased resistance to taxol and VP16, and higher levels of genes involved in nucleotide excision repair partially explain the resistance to cisplatin. These cells express mesenchymal markers, and epithelial transition could be induced when cultured in differentiating conditions, with a loss of invasive potential. These data suggest that ovarian cancer is a stem cell disease and should help elucidate the role of these cells in the aggressive phenotype of this tumor and find new therapeutic strategies to reduce resistance to current chemotherapeutic drugs.
Cell cycle (Georgetown, Tex.) 05/2012; 11(10):1966-76. · 5.36 Impact Factor
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ABSTRACT: Epithelial ovarian cancer is a malignancy with high rate of death due to an advanced disease at diagnosis and frequent relapse after chemotherapy. Nowadays, there is a lack of knowledge for clear risk factors and predictive and/or prognostic genetic markers although genomic alterations such as mutations in p53, PTEN, BRCA1/BRCA2, HER2, KRAS and PI3K genes have been associated to this pathology. A genomic variant in the 3' untraslated region of cancer related gene KRAS, is able to disrupt the let-7 miRNA binding site. The SNP, commonly named KRAS-LCS6, determines the substitution of the more abundant T-allele to a G-allele which was observed to increase the KRAS expression and in turn to activate the downstream pathway at higher levels if compared to the T-allele. In this study we assessed the role of the KRAS-LCS6 polymorphism (rs61764370) in 97 early (stages I and II) and 232 advanced (stages III and IV) ovarian cancer patients in order to associate this SNP to any physiopathological characteristic of the patients cohort, including progression free survival and overall survival, with a follow up data longer than ten years. Our data indicate that KRAS-LCS6 polymorphism is not relevant in ovarian cancer, in fact, in our cohort of patients, is not associated to any outcome or physiopathological characteristic.
American journal of cancer research. 01/2012; 2(3):298-308.
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ABSTRACT: Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor-bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA (shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer.
Molecular Cancer Therapeutics 01/2012; 11(1):214-23. · 5.23 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In this process, cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Such transformation has implications in progression of breast carcinoma to metastasis, and increasing evidences support most tumors contain a subpopulation of cells with stem-like and mesenchymal features that is resistant to chemotherapy. This review focuses on the physiological and pathological role of EMT process, its molecular related network, its putative role in the metastatic process and its implications in response/resistance to the current and/or new approaching drugs in the clinical management of breast cancer.
Cancer treatment reviews 11/2011; 38(6):689-97. · 5.30 Impact Factor
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Katherine S Lovejoy,
Maria Serova,
Ivan Bieche,
Shahin Emami,
Maurizio D'Incalci, Massimo Broggini,
Eugenio Erba,
Christian Gespach,
Esteban Cvitkovic,
Sandrine Faivre,
Eric Raymond,
Stephen J Lippard
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ABSTRACT: Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use.
Molecular Cancer Therapeutics 07/2011; 10(9):1709-19. · 5.23 Impact Factor
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ABSTRACT: The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is a major target for cancer therapy. As a strategy to induce the maximal inhibition of this pathway in cancer cells, we combined allosteric mTOR inhibitors (rapamycin and RAD001) with a dual PI3K/mTOR kinase inhibitor (PI-103). Both in vitro and in vivo, the combination exhibited more activity than single agents in human ovarian and prostate cancer cells that harbor alterations in the pathway. At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation. Furthermore, the combination strongly inhibited the expression of PI3K/Akt/mTOR downstream proteins. In particular, it showed greater activity than the single agents in inhibiting the phosphorylation of 4EBP1, both in vitro and in vivo, resulting in selective inhibition of CAP-dependent translation. A proteomic approach was used to confirm the identification of c-Myc as the key regulator for the reduction in downstream proteins affected by the combined inhibition of mTOR. In conclusion, the combination of a catalytic and an allosteric inhibitor of mTOR shows greater activity, without a concomitant increase in toxicity, than either drug alone, and this may have therapeutic implications for inhibiting this pathway in the clinical setting.
Cancer Research 05/2011; 71(13):4573-84. · 7.86 Impact Factor
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ABSTRACT: Cancer is a complex cellular disease caused by multiple factors via genetic mutations (hereditary or somatic) or environmental factors. The emerging omics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, and interactomics, are increasingly being used for cancer research and personalized medicine; they have provided new opportunities in the molecular analysis of human cancer with unprecedented speed and detail. The omic approach has brought powerful ability to screen cancer cells at different levels from gene to metabolite and to search for novel drug targets, expounding the drug mechanism of action, identifying adverse effects in unexpected interaction, validating current drug targets, exploring potential applications for novel drugs, and enabling the translation from bench to bedside. As a clinical research tool, the neoadjuvant approach in breast cancer is the perfect setting for individualization of treatment based on clinical, pathological, image-guided, or molecular assessment, based on the omics techniques of tumors during treatment; neoadjuvant treatment offers the ability to discern treatment effect in vivo and may allow smaller trials targeting specific breast cancer subtypes.
JNCI Monographs 01/2011; 2011(43):128-33.
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Journal of Clinical Oncology 09/2010; 28(27):e467; author reply e468. · 18.37 Impact Factor
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ABSTRACT: Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc(Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc(Min) or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc(Min) mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc(Min) and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents.
Cancer Prevention Research 08/2010; 3(8):929-39. · 4.91 Impact Factor
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ABSTRACT: Increased activity of Sp family of transcription factors is a frequent and critical event in cancer development and progression. Genes governing tumor growth, invasion and angiogenesis are regulated by Sp factors, like Sp1, Sp3 or Sp4, and are frequently over-expressed in tumors. Targeting Sp factors has been explored as a therapeutic approach. Mithramycin (MTM) is a natural antibiotic that binds DNA and inhibit Sp1-dependent transcription. New analogues, named MTM-SDK and MTM-SK, were recently obtained by genetic engineering of the MTM biosynthetic pathway and have demonstrated improved transcriptional and antiproliferative activity in ovarian cancer cell lines in vitro. In the present study we evaluated the activity of the new compounds in human ovarian cancer xenografts.
Expression of Sp1 and target proteins in ovarian cancer specimens and tumor xenografts was assessed by immunohistochemistry. Drug-induced silencing of Sp1-regulated genes in cells and tumor xenograft samples was assessed by quantitative RT-PCR. Toxicity and antitumor activity of the compounds were investigated in healthy and tumor-bearing immunocompromised mice, respectively.
Expression of Sp1 was frequently increased in human epithelial ovarian cancers. MTM-SDK and MTM-SK acted as potent inhibitors of Sp1-dependent transcription both in vitro and in tumor xenografts. Both compounds were well tolerated even after prolonged administration and delayed growth of ovarian tumor xenografts. MTM-SDK was particularly effective against orthotopic tumors leading to a significant increase of survival and delay of tumor progression.
MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers.
Gynecologic Oncology 05/2010; 118(2):182-8. · 3.89 Impact Factor
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ABSTRACT: To clarify the reciprocal interaction between human-breast cancer metastatic cells and bone microenvironment, we studied the influence of HGF/Met system on a proposed-prognostic marker of aggressiveness, the beta-catenin/Wnt pathway. For in vitro and in vivo experiments we used 1833-bone metastatic clone, derived from human-MDA-MB231 cells. In osteolytic bone metastases and in metastatic cells, Met was expressed in nuclei and at plasma membrane, and abnormally co-localised at nuclear level with beta-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and beta-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of beta-catenin functionality. In 1833 cells, human and mouse HGF increased Met and beta-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, beta-catenin nuclear translocation via Kank and TOPFLASH transactivation. Human HGF was autocrine/intracrine in bone metastasis, and mouse HGF originating from the adjacent host-bone marrow, was found inside the metastatic nuclei. Parental MDA-MB231 cell nuclei did not show functional beta-catenin, for TCF-transactivating activity, and the regulation by HGF. Our study highlighted the importance of the metastasis-stroma interaction in human-breast cancer metastatisation and first identified the HGF/nuclear Met/phospho-c-Src/beta-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.
European journal of cancer (Oxford, England: 1990) 03/2010; 46(9):1679-91. · 4.12 Impact Factor
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ABSTRACT: Hematopoietic stem cells (HSC) isolated from umbilical cord blood (UCB) were treated with ionizing radiation (IR) and sensitivity and IR induced checkpoints activation were investigated. No difference in the sensitivity and in the activation of DNA damage pathways was observed between CD133+ HSC and cells derived from them after ex vivo expansion. Chk1 protein was very low in freshly isolated CD133+ cells, and undetectable in ex vivo expanded UCB CD133+ cells. Chk1 was expressed only on day 3 of the ex vivo expansion. This pattern of Chk1 expression was corroborated in CD133+ cells isolated from peripheral blood apheresis collected from an healthy donor. Treatment with a specific Chk1 inhibitor resulted in a strong reduction in the percentage of myeloid precursors (CD33+) and an increase in the percentage of lymphoid precursors (CD38+) compared to untreated cells, suggesting a possible role for Chk1 in the differentiation program of UCB CD133+ HSC.
Cellular and Molecular Life Sciences CMLS 02/2010; 67(10):1713-22. · 6.57 Impact Factor
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ABSTRACT: Abstract Background Drug resistance is one of the major obstacles limiting the activity of anticancer agents. Activation of DNA repair mechanism often accounts for increase resistance to cancer chemotherapy. Results We present evidence that nemorubicin, a doxorubicin derivative currently in clinical evaluation, acts through a mechanism of action different from classical anthracyclines, requiring an intact nucleotide excision repair (NER) system to exert its activity. Cells made resistant to nemorubicin show increased sensitivity to UV damage. We have analysed the mechanism of resistance and discovered a previously unknown mechanism resulting from methylation-dependent silencing of the XPG gene. Restoration of NER activity through XPG gene transfer or treatment with demethylating agents restored sensitivity to nemorubicin. Furthermore, we found that a significant proportion of ovarian tumors present methylation of the XPG promoter. Conclusions Methylation of a NER gene, as described here, is a completely new mechanism of drug resistance and this is the first evidence that XPG gene expression can be influenced by an epigenetic mechanism. The reported methylation of XPG gene could be an important determinant of the response to platinum based therapy. In addition, the mechanism of resistance reported opens up the possibility of reverting the resistant phenotype using combinations with demethylating agents, molecules already employed in the clinical setting.
Molecular Cancer. 01/2010;
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ABSTRACT: Drug resistance is one of the major obstacles limiting the activity of anticancer agents. Activation of DNA repair mechanism often accounts for increase resistance to cancer chemotherapy.
We present evidence that nemorubicin, a doxorubicin derivative currently in clinical evaluation, acts through a mechanism of action different from classical anthracyclines, requiring an intact nucleotide excision repair (NER) system to exert its activity. Cells made resistant to nemorubicin show increased sensitivity to UV damage. We have analysed the mechanism of resistance and discovered a previously unknown mechanism resulting from methylation-dependent silencing of the XPG gene. Restoration of NER activity through XPG gene transfer or treatment with demethylating agents restored sensitivity to nemorubicin. Furthermore, we found that a significant proportion of ovarian tumors present methylation of the XPG promoter.
Methylation of a NER gene, as described here, is a completely new mechanism of drug resistance and this is the first evidence that XPG gene expression can be influenced by an epigenetic mechanism. The reported methylation of XPG gene could be an important determinant of the response to platinum based therapy. In addition, the mechanism of resistance reported opens up the possibility of reverting the resistant phenotype using combinations with demethylating agents, molecules already employed in the clinical setting.
Molecular Cancer 01/2010; 9:259. · 3.99 Impact Factor
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Silvia Pezzola,
Giovanni Antonini,
Cristina Geroni,
Italo Beria,
Maristella Colombo, Massimo Broggini,
Sergio Marchini,
Nicola Mongelli,
Loris Leboffe,
Robert MacArthur,
Alessia Francesca Mozzi,
Giorgio Federici,
Anna Maria Caccuri
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ABSTRACT: Brostallicin is a novel and unique glutathione transferase-activated pro-drug with promising anticancer activity, currently in phase I and II clinical evaluation. In this work, we show that, in comparison with the parental cell line showing low GST levels, the cytotoxic activity of brostallicin is significantly enhanced in the human breast carcinoma MCF-7 cell line, transfected with either human GST-pi or GST-mu. Moreover, we describe in detail the interaction of brostallicin with GSH in the presence of GSTP1-1 and GSTM2-2, the predominant GST isoenzymes found within tumor cells. The experiments reported here indicate that brostallicin binds reversibly to both isoenzymes with K(d) values in the micromolar range (the affinity being higher for GSTM2-2). Direct evidence that both GSTP1-1 and GSTM2-2 isoenzymes catalyze the Michael addition reaction of GSH to brostallicin has been obtained both by an HPLC-MS technique and by a new fluorometric assay. We also saw the rapid formation of an intermediate reactive species, which is slowly converted into the final products. This intermediate, identified as the alpha-chloroamido derivative of the GSH-brostallicin adduct, is able to alkylate DNA in a sequence-specific manner and appears to be the active form of the drug. The kinetic behavior of the reaction between brostallicin and GSH, catalyzed by GSTP1-1, has been studied in detail, and a minimum kinetic scheme that suitably describes the experimental data is provided. Overall, these data fully support and extend the findings that brostallicin could be indicated for the treatment of tumor overexpressing the pi or mu class GST.
Biochemistry 12/2009; 49(1):226-35. · 3.42 Impact Factor
