Pub Date : 2019-09-20DOI: 10.31083/J.JMCM.2019.03.0303
S. Narayanan, Q. Teng, J. Koya, Jing-Quan Wang, Y. Assaraf, C. Ashby, Zhe-Sheng, Chen
Poly (ADP-ribose) polymerase (PARP) proteins mediate various cellular processes such as DNA repair, regulation of transcription, protein-protein interaction, expression of inflammatory genes and programmed cell death. PARP proteins have a key role in DNA repair and recent findings have established the role of PARP inhibitors as potent chemotherapeutic drugs. Among the 18 members, PARP1 and PARP2 have been identified as the main targets for the development of pharmacological inhibitors to enhance the cytotoxic efficacy of established anticancer drugs. Furthermore, certain PARP1 and PARP2 inhibitors are being used in combination with other drugs for the treatment of various types of cancer. In different drug resistant cancer cell types, PARP inhibitors have been identified as compounds that reverse the resistance to topoisomerase inhibitors, DNA alkylating and methylating drugs by enhancing the DNA damage induced by these agents. In BRCA mutant cells, with abnormal homologous recombination (HR) repair mechanism, BER (Base Excision Repair Pathway) is responsible for survival of the cells. PARP enzymes play a major role in BER and PARP inhibitors effectively target BRCA mutant cells sparing normal cells via the concept of synthetic lethality, producing minimal toxicity to PARP inhibitors also have a significant role in treating pancreatic adenocarcinoma and castration-resistant prostate cancer. The aim of the current paper is to provide a review on PARP inhibitors and their application in the treatment of various cancer cells which are resistant to standard chemotherapeutic drugs. Keywords
{"title":"Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers","authors":"S. Narayanan, Q. Teng, J. Koya, Jing-Quan Wang, Y. Assaraf, C. Ashby, Zhe-Sheng, Chen","doi":"10.31083/J.JMCM.2019.03.0303","DOIUrl":"https://doi.org/10.31083/J.JMCM.2019.03.0303","url":null,"abstract":"Poly (ADP-ribose) polymerase (PARP) proteins mediate various cellular processes such as DNA repair, regulation of transcription, protein-protein interaction, expression of inflammatory genes and programmed cell death. PARP proteins have a key role in DNA repair and recent findings have established the role of PARP inhibitors as potent chemotherapeutic drugs. Among the 18 members, PARP1 and PARP2 have been identified as the main targets for the development of pharmacological inhibitors to enhance the cytotoxic efficacy of established anticancer drugs. Furthermore, certain PARP1 and PARP2 inhibitors are being used in combination with other drugs for the treatment of various types of cancer. In different drug resistant cancer cell types, PARP inhibitors have been identified as compounds that reverse the resistance to topoisomerase inhibitors, DNA alkylating and methylating drugs by enhancing the DNA damage induced by these agents. In BRCA mutant cells, with abnormal homologous recombination (HR) repair mechanism, BER (Base Excision Repair Pathway) is responsible for survival of the cells. PARP enzymes play a major role in BER and PARP inhibitors effectively target BRCA mutant cells sparing normal cells via the concept of synthetic lethality, producing minimal toxicity to PARP inhibitors also have a significant role in treating pancreatic adenocarcinoma and castration-resistant prostate cancer. The aim of the current paper is to provide a review on PARP inhibitors and their application in the treatment of various cancer cells which are resistant to standard chemotherapeutic drugs. Keywords","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87045894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-20DOI: 10.31083/J.JMCM.2019.03.0302
S. Eline, V. Jasper, Hulleman Esther
Tumors of the central nervous system (CNS) are the main cause of cancer-related death in children. While improvements in survival rates for various childhood cancers have been obtained over the last decades, little progress has been made for pediatric brain tumors. In addition, current conventional treatment gives rise to severe long term toxicity, which underpins the burning need for the development of novel therapeutic modalities. Immunotherapy was shown to be successful in both adult solid tumors and pediatric hemato-oncology, and may be an option for pediatric CNS malignancies. However, pediatric brain tumors have a strong immunosuppressive microenvironment, which is considered a major hurdle for effective immunotherapy. The low mutational burden of these tumors may compromise immunotherapy for this patient group even further. The possibility to directly apply the current immune modulating therapies directly into the tumor, however, opens new options for immunotherapy in this population. This review covers immunotherapeutic approaches including immune checkpoint inhibition, chimeric antigen receptor T (CAR-T) cell therapy, therapeutic cancer vaccines, and oncolytic virotherapy. We review their effect on the immunosuppressive tumor microenvironment, summarize current trials, and discuss future directions. We conclude that immunotherapy holds promise for children with CNS malignancies, especially when combined with different (immune) therapeutic strategies.
{"title":"Immunotherapy in pediatric brain tumors: considerations, challenges and future directions","authors":"S. Eline, V. Jasper, Hulleman Esther","doi":"10.31083/J.JMCM.2019.03.0302","DOIUrl":"https://doi.org/10.31083/J.JMCM.2019.03.0302","url":null,"abstract":"Tumors of the central nervous system (CNS) are the main cause of cancer-related death in children. While improvements in survival rates for various childhood cancers have been obtained over the last decades, little progress has been made for pediatric brain tumors. In addition, current conventional treatment gives rise to severe long term toxicity, which underpins the burning need for the development of novel therapeutic modalities. Immunotherapy was shown to be successful in both adult solid tumors and pediatric hemato-oncology, and may be an option for pediatric CNS malignancies. However, pediatric brain tumors have a strong immunosuppressive microenvironment, which is considered a major hurdle for effective immunotherapy. The low mutational burden of these tumors may compromise immunotherapy for this patient group even further. The possibility to directly apply the current immune modulating therapies directly into the tumor, however, opens new options for immunotherapy in this population. This review covers immunotherapeutic approaches including immune checkpoint inhibition, chimeric antigen receptor T (CAR-T) cell therapy, therapeutic cancer vaccines, and oncolytic virotherapy. We review their effect on the immunosuppressive tumor microenvironment, summarize current trials, and discuss future directions. We conclude that immunotherapy holds promise for children with CNS malignancies, especially when combined with different (immune) therapeutic strategies.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87156064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-20DOI: 10.31083/J.JMCM.2019.03.0213
Zisman Ariel, Nativ Omri, Malshy Kamil, Sadeh Omer, A. Tareq, Shabataev Valentin, Hoffman Azik, Mullerad Michael, E. Gilad
Introduction: Robotic partial nephrectomy (RPN) is a relatively safe nephron sparing surgery (NSS) approach for the treatment of small renal masses (cT1). However, a major perioperative complication is extensive bleeding and blood loss necessitating blood transfusion. This complication is most challenging during the intraoperative setting and requires proper tumor bed closure. Recently several biological tissue adhesives have been tested to decrease intraoperative bleeding. A novel adhesive, Starsil® Hemostat is a plant-derived polysaccharide that can be applied directly to a bleeding wound to achieve hemostasis. The aim of our current study was to perform an evaluation of the safety and efficacy of this novel hemostat in patients undergoing RPN. Methods: This prospective single arm study included twenty patients with T1a-T1b renal masses who underwent RPN between the years 20172018. Renal masses were classified according to size, exophytic/endophytic properties and anatomic location into low, moderate and high complexity cases as described by the R.E.N.A.L nephrometry score. Starsil® Hemostat was applied by a feeding tube through a laparoscopic port after tumor excision. Perioperative data were collected, including blood loss during surgery, blood product transfusion rates, short and long-term adverse events and surgeon satisfaction using a visual analog scale (VAS 1-10). Results: Twenty RPN surgeries were completed using the Starsil® Hemostat. The average age was 61.8 ±14.3. Average maximal tumor diameter was 3.8 cm (range 1.55.7). The calculated mean R.E.N.A.L nephrometry score was 8.4 (range 5-12). Mean blood loss during surgery was 346 mL (range 50-1400 mL). Mean surgeon satisfaction (VAS 1-10) with bleeding control was 8.3, when recorded 24 hours post operation. In 17/20 procedures (85%), bleeding control was good (VAS 9-10) and only 2 patients required blood transfusion. None of the patients developed an allergic reaction. No adverse events related to the adhesive product were noted in the post-surgical follow up period. Conclusion: Tumor bed closure during NSS with the adhesive STARSIL® Hemostat is safe, feasible and easy to use. It has the potential to reduce blood loss and transfusion rate in patients undergoing RPN. Keywords
{"title":"The use of biological glue (Starsil® Hemostat) in robotic partial nephrectomy: a safety and efficacy study","authors":"Zisman Ariel, Nativ Omri, Malshy Kamil, Sadeh Omer, A. Tareq, Shabataev Valentin, Hoffman Azik, Mullerad Michael, E. Gilad","doi":"10.31083/J.JMCM.2019.03.0213","DOIUrl":"https://doi.org/10.31083/J.JMCM.2019.03.0213","url":null,"abstract":"Introduction: Robotic partial nephrectomy (RPN) is a relatively safe nephron sparing surgery (NSS) approach for the treatment of small renal masses (cT1). However, a major perioperative complication is extensive bleeding and blood loss necessitating blood transfusion. This complication is most challenging during the intraoperative setting and requires proper tumor bed closure. Recently several biological tissue adhesives have been tested to decrease intraoperative bleeding. A novel adhesive, Starsil® Hemostat is a plant-derived polysaccharide that can be applied directly to a bleeding wound to achieve hemostasis. The aim of our current study was to perform an evaluation of the safety and efficacy of this novel hemostat in patients undergoing RPN. Methods: This prospective single arm study included twenty patients with T1a-T1b renal masses who underwent RPN between the years 20172018. Renal masses were classified according to size, exophytic/endophytic properties and anatomic location into low, moderate and high complexity cases as described by the R.E.N.A.L nephrometry score. Starsil® Hemostat was applied by a feeding tube through a laparoscopic port after tumor excision. Perioperative data were collected, including blood loss during surgery, blood product transfusion rates, short and long-term adverse events and surgeon satisfaction using a visual analog scale (VAS 1-10). Results: Twenty RPN surgeries were completed using the Starsil® Hemostat. The average age was 61.8 ±14.3. Average maximal tumor diameter was 3.8 cm (range 1.55.7). The calculated mean R.E.N.A.L nephrometry score was 8.4 (range 5-12). Mean blood loss during surgery was 346 mL (range 50-1400 mL). Mean surgeon satisfaction (VAS 1-10) with bleeding control was 8.3, when recorded 24 hours post operation. In 17/20 procedures (85%), bleeding control was good (VAS 9-10) and only 2 patients required blood transfusion. None of the patients developed an allergic reaction. No adverse events related to the adhesive product were noted in the post-surgical follow up period. Conclusion: Tumor bed closure during NSS with the adhesive STARSIL® Hemostat is safe, feasible and easy to use. It has the potential to reduce blood loss and transfusion rate in patients undergoing RPN. Keywords","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84844996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-20DOI: 10.31083/J.JMCM.2019.03.0301
Pranav Gupta, Yunali V. Ashar, Q. Teng, Z. Lei, Bryan Chen, Sandra E. Reznik, J. Wurpel, Zhe-Sheng, Chen
The development of multidrug resistance (MDR) due to the overexpression of ATP-binding cassette (ABC) transporters remains one of the major obstacles to the success of chemotherapy in clinics. It is of paramount importance to identify novel drug combinations that could inhibit the multidrug efflux of ABC transporters and enhance the chemo-sensitivity of substrate anticancer drugs. In this study, we evaluated avapritinib, a KIT and PDGFRA blocker, for its reversal effects on the drug sensitivity of ABCB1 and ABCG2 overexpressing cells. Our results show that avapritinib significantly enhanced the cytotoxicity of the substrates of both ABCB1 and ABCG2. Mechanistic studies revealed that avapritinib enhances the intracellular accumulation of the substrates of ABCB1 or ABCG2 by directly decreasing their efflux from the cells overexpressing ABCB1 or ABCG2. Moreover, avapritinib did not change the expressional levels or translocation of ABCB1 or ABCG2 protein from the cell membrane to the cytoplasm and stimulates the ATP cleaving activity of both ABCB1 and ABCG2. Taken together, our results open new avenues for the use of avapritinib as cancer chemotherapy, when used in combination with the substrates of ABCB1 or ABCG2.
{"title":"KIT and PDGFRA inhibitor avapritinib (BLU-285) overcomes ABCB1- and ABCBG2-mediated MDR in cancer cells","authors":"Pranav Gupta, Yunali V. Ashar, Q. Teng, Z. Lei, Bryan Chen, Sandra E. Reznik, J. Wurpel, Zhe-Sheng, Chen","doi":"10.31083/J.JMCM.2019.03.0301","DOIUrl":"https://doi.org/10.31083/J.JMCM.2019.03.0301","url":null,"abstract":"The development of multidrug resistance (MDR) due to the overexpression of ATP-binding cassette (ABC) transporters remains one of the major obstacles to the success of chemotherapy in clinics. It is of paramount importance to identify novel drug combinations that could inhibit the multidrug efflux of ABC transporters and enhance the chemo-sensitivity of substrate anticancer drugs. In this study, we evaluated avapritinib, a KIT and PDGFRA blocker, for its reversal effects on the drug sensitivity of ABCB1 and ABCG2 overexpressing cells. Our results show that avapritinib significantly enhanced the cytotoxicity of the substrates of both ABCB1 and ABCG2. Mechanistic studies revealed that avapritinib enhances the intracellular accumulation of the substrates of ABCB1 or ABCG2 by directly decreasing their efflux from the cells overexpressing ABCB1 or ABCG2. Moreover, avapritinib did not change the expressional levels or translocation of ABCB1 or ABCG2 protein from the cell membrane to the cytoplasm and stimulates the ATP cleaving activity of both ABCB1 and ABCG2. Taken together, our results open new avenues for the use of avapritinib as cancer chemotherapy, when used in combination with the substrates of ABCB1 or ABCG2.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82390419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-04-20DOI: 10.31083/j.jmcm.2019.02.9161
Xin Cao, Quanlin An, Y. Assaraf, Xiangdong Wang
All trans-retinoic acid (ATRA) as well as several key retinoids including tamibarotene, acyclic retinoid (ACR), and WYC-209, have made a major progress in both preclinical cancer therapeutics as well as in the clinical setting regarding the treatment of leukemia and solid tumors via their important impacts on cancer stem cell differentiation or apoptosis. ATRA exerts its antitumor activity by binding to retinoic acid receptors, which in turn specifically bind to DNA as a heterodimer with the retinoid X receptors, at promoter regions known as retinoic acid response elements. The impressive new studies and clinical achievements with retinoids as key pre-clinical research tools and antitumor agents, are summarized and discussed in the current paper. The ongoing clinical trial of tamibarotene, which is the first agent targeting super-enhancers-containing cancers, could provide a new treatment modality for acute myeloid leukemia patients. A recent clinical study for evaluation of the preventive effects of ACR on second primary hepatocellular carcinoma (HCC) demonstrated that the oral administration of ACR for 12 months, significantly reduced HCC recurrence. WYC-209 strongly inhibited cell proliferation of different tumor repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, and also blocked > 80% of B16 TRCs' lung metastases in wild-type C57BL/6 mice, without any apparent toxicity. These remarkable findings reveal that retinoids constitute a promising class of antitumor agents for the treatment of both hematological malignancies and solid tumors. Keywords
{"title":"Retinoids offer new and promising cancer therapeutic avenues","authors":"Xin Cao, Quanlin An, Y. Assaraf, Xiangdong Wang","doi":"10.31083/j.jmcm.2019.02.9161","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.02.9161","url":null,"abstract":"All trans-retinoic acid (ATRA) as well as several key retinoids including tamibarotene, acyclic retinoid (ACR), and WYC-209, have made a major progress in both preclinical cancer therapeutics as well as in the clinical setting regarding the treatment of leukemia and solid tumors via their important impacts on cancer stem cell differentiation or apoptosis. ATRA exerts its antitumor activity by binding to retinoic acid receptors, which in turn specifically bind to DNA as a heterodimer with the retinoid X receptors, at promoter regions known as retinoic acid response elements. The impressive new studies and clinical achievements with retinoids as key pre-clinical research tools and antitumor agents, are summarized and discussed in the current paper. The ongoing clinical trial of tamibarotene, which is the first agent targeting super-enhancers-containing cancers, could provide a new treatment modality for acute myeloid leukemia patients. A recent clinical study for evaluation of the preventive effects of ACR on second primary hepatocellular carcinoma (HCC) demonstrated that the oral administration of ACR for 12 months, significantly reduced HCC recurrence. WYC-209 strongly inhibited cell proliferation of different tumor repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, and also blocked > 80% of B16 TRCs' lung metastases in wild-type C57BL/6 mice, without any apparent toxicity. These remarkable findings reveal that retinoids constitute a promising class of antitumor agents for the treatment of both hematological malignancies and solid tumors. Keywords","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84279083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-04-20DOI: 10.31083/j.jmcm.2019.02.151
Darko Durovski, O. Randazzo, G. Peters, E. Giovannetti
Darko Durovski1,2, Ornella Randazzo1,5, Godefridus J. Peters1,3 and Elisa Giovannetti1,4,∗ 1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081HV, The Netherlands 2Amsterdam University College, Amsterdam 1098XG, The Netherlands 3Department of Biochemistry, Medical University of Gdansk, Gdansk 80-4161, Poland 4Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa 56017, Italy 5Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo 90123, Italy
{"title":"The role of developmental signaling pathways in non-small cell lung carcinoma","authors":"Darko Durovski, O. Randazzo, G. Peters, E. Giovannetti","doi":"10.31083/j.jmcm.2019.02.151","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.02.151","url":null,"abstract":"Darko Durovski1,2, Ornella Randazzo1,5, Godefridus J. Peters1,3 and Elisa Giovannetti1,4,∗ 1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081HV, The Netherlands 2Amsterdam University College, Amsterdam 1098XG, The Netherlands 3Department of Biochemistry, Medical University of Gdansk, Gdansk 80-4161, Poland 4Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa 56017, Italy 5Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo 90123, Italy","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84319220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-04-20DOI: 10.31083/j.jmcm.2019.02.7161
Lopes-Rodrigues Vanessa, P. Cristina, S. Diana, Osório Hugo, G. Yehuda, T. Raquel, M. Vasconcelos
Porto, 4099-003 Porto, Portugal 4Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, 4050-313 Porto, Portugal 5Department of Oncology, FMUP–Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal 6IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal 7The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200000
{"title":"ALIX protein analysis: storage temperature may impair results","authors":"Lopes-Rodrigues Vanessa, P. Cristina, S. Diana, Osório Hugo, G. Yehuda, T. Raquel, M. Vasconcelos","doi":"10.31083/j.jmcm.2019.02.7161","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.02.7161","url":null,"abstract":"Porto, 4099-003 Porto, Portugal 4Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, 4050-313 Porto, Portugal 5Department of Oncology, FMUP–Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal 6IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal 7The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200000","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81673598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-04-20DOI: 10.31083/j.jmcm.2019.02.7181
P. Adrián, R. Alexis, A. Roderick, Demanuele Kaylie, X. F. Miguel, Bosica Giovanna, M. José
Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na+and Cl−dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α -methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJhTERT.
{"title":"Naphthol-derived Betti bases as potential SLC6A14 blockers","authors":"P. Adrián, R. Alexis, A. Roderick, Demanuele Kaylie, X. F. Miguel, Bosica Giovanna, M. José","doi":"10.31083/j.jmcm.2019.02.7181","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.02.7181","url":null,"abstract":"Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na+and Cl−dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α -methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJhTERT.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87558843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-01-20DOI: 10.31083/j.jmcm.2019.01.6161
Gazzano Elena, Kopecka Joanna, D.B. Carolina, C. Costanzo, R. Chiara
One of the chemotherapeutic drugs in the first-line treatment of osteosarcoma is doxorubicin (dox). However, its anticancer efficacy is limited by the overexpression of the multidrug efflux transporter P-glycoprotein (Pgp) which extrudes doxorubicin, disrupts drug accumulation and thus hinders the cytotoxic activity of dox. The drug extrusion activity of Pgp is enhanced by the presence of cholesterol within the plasma membrane. Pgp expression is up-regulated by multiple transcription factors including hypoxia inducible factor-1α (HIF-1α). Decreasing Pgp expression and drug efflux activity may enhance the efficacy of doxorubicin against drug resistant osteosarcoma. To achieve this goal, we treated two human dox-sensitive cell lines (U-2OS and Saos-2), and their sublines displaying increasing Pgp levels and dox resistance, with a non-toxic dose of atorvastatin. This statin was able to decrease the biosynthesis of farnesyl pyrophosphate (FPP) and cholesterol, two key metabolites that were markedly increased in drug resistant sublines. By reducing the FPP levels, atorvastatin decreased the Ras/ERK1/2/HIF-1α axis and down-regulated Pgp expression. Moreover, by decreasing cholesterol biosynthesis atorvastatin increased the levels of low density lipoprotein receptor (LDLR), that was also progressively increased in the dox-resistant sublines. Taking advantage of this findings, we treated dox-resistant osteosarcoma with atorvastatin followed by treatment with dox encapsulated in liposomes decorated with an LDLRbinding peptide, hence facilitating binding to, and endocytosis via LDLR. This treatment strategy induced high retention of dox in dox-resistant cells, reduced cell viability in vitro and displayed growth inhibition of dox-resistance in mouse xenograft model. Hence, we propose the combination of statins plus LDL-decorated liposomal dox as a novel treatment strategy for Pgp-expressing multidrug resistant osteosarcomas.
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Pub Date : 2019-01-20DOI: 10.31083/j.jmcm.2019.01.7261
Shprits Sagi, S. Robert, Croitoru Simona, Dorfman Karina, Avitan Ofir, B. Zaher, Zisman Amnon, Nativ Ofer
The growing use and improvement of imaging modalities has resulted in increased detection of renal tumors. The gold standard treatment of small renal masses is nephronsparing surgery. Such surgical intervention is associated with significant rate of local failure. The currently accepted treatment for local failure after nephron-sparing surgery is radical nephrectomy which is associated with very high complication rate as well as loss of functional renal parenchyma. The aim of the current study was to evaluate the safety, technical feasibility, oncologic success and functional preservation of percutaneous cryoablation using a new liquid nitrogen-based cryogenic device in patients with tumor recurrence after nephron-sparing surgery. We present seven patients with tumor recurrence after nephron-sparing surgery who underwent percutaneous cryoablation using ProSenseTM (IceCure Medical Ltd, Caesarea, Israel) under computerized tomography guidance. None of the treated tumor lesions demonstrated contrast enhancement or growth on follow up imaging indicating a 100% oncologic success. Only three adverse events were recorded, all were classified as low grade and resolved spontaneously. In conclusion, percutaneous cryoablation using the novel ProSenseTM device for recurrent renal tumors following nephron-sparing surgery is feasible and effective, with excellent renal function preservation and without major complications.
越来越多的使用和改进的成像方式导致肾脏肿瘤的检测增加。小肾肿块的金标准治疗是肾保留手术。这种手术干预与显著的局部失败率相关。对于保留肾的手术后局部衰竭，目前公认的治疗方法是根治性肾切除术，但根治性肾切除术的并发症发生率很高，并伴有功能性肾实质的丧失。本研究的目的是评估一种新型液氮低温装置在肾保留手术后肿瘤复发患者中经皮冷冻消融的安全性、技术可行性、肿瘤学成功和功能保存。我们报告了7例肾保留手术后肿瘤复发的患者，他们在计算机断层扫描指导下使用ProSenseTM (IceCure Medical Ltd, Caesarea, Israel)进行经皮冷冻消融。治疗后的肿瘤病变均未在随访影像中显示造影剂增强或生长，这表明肿瘤治疗100%成功。仅记录了3例不良事件，均为低级别并自行消退。综上所述，新型ProSenseTM装置经皮冷冻消融治疗肾肿瘤保留肾单位手术后复发是可行和有效的，具有良好的肾功能保存和无重大并发症。
{"title":"Cryoablation for recurrent renal tumors after primary nephron-sparing surgery using an innovative liquid nitrogen-based cryogenic device","authors":"Shprits Sagi, S. Robert, Croitoru Simona, Dorfman Karina, Avitan Ofir, B. Zaher, Zisman Amnon, Nativ Ofer","doi":"10.31083/j.jmcm.2019.01.7261","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.01.7261","url":null,"abstract":"The growing use and improvement of imaging modalities has resulted in increased detection of renal tumors. The gold standard treatment of small renal masses is nephronsparing surgery. Such surgical intervention is associated with significant rate of local failure. The currently accepted treatment for local failure after nephron-sparing surgery is radical nephrectomy which is associated with very high complication rate as well as loss of functional renal parenchyma. The aim of the current study was to evaluate the safety, technical feasibility, oncologic success and functional preservation of percutaneous cryoablation using a new liquid nitrogen-based cryogenic device in patients with tumor recurrence after nephron-sparing surgery. We present seven patients with tumor recurrence after nephron-sparing surgery who underwent percutaneous cryoablation using ProSenseTM (IceCure Medical Ltd, Caesarea, Israel) under computerized tomography guidance. None of the treated tumor lesions demonstrated contrast enhancement or growth on follow up imaging indicating a 100% oncologic success. Only three adverse events were recorded, all were classified as low grade and resolved spontaneously. In conclusion, percutaneous cryoablation using the novel ProSenseTM device for recurrent renal tumors following nephron-sparing surgery is feasible and effective, with excellent renal function preservation and without major complications.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86205304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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