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Πέμπτη 18 Ιουλίου 2019

Anti-Cancer Drugs

Melanoma: the new perspectives from clinical and translational research
imageThe prognosis of metastatic melanoma has not changed throughout the 20th century. However, in the last decade, we have witnessed a continuous improvement in survival, with many long-term survivors. These results are largely because of the simultaneous development of the knowledge in the biology of metastatic malignant melanoma and of the relationship between the disease and the host's immune system that allowed the development of effective new treatments. In this overview, we summarize the therapies available today, their biological rationale, and the research field currently under investigation divided into three main chapters: target therapies, immunotherapies, and their combination.

Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer
imageOvarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.

Knockdown of long noncoding RNA-taurine-upregulated gene 1 inhibits tumor angiogenesis in ovarian cancer by regulating leucine-rich α-2-glycoprotein-1
imageTo investigate the role of long noncoding RNA taurine-upregulated gene 1 (TUG1) on ovarian cancer-induced angiogenesis and to explore possible signaling pathways. Ovarian cancer cell line SKOV3 or CAOV3 was transfected with short hairpin-TUG1 to suppress TUG1 expression. Supernatant from cultured cancer cells was used as a condition medium to incubate endothelial cell line human umbilical vein endothelial cells, whose proliferation rate was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Migration and invasion of endothelial cells were examined by wound healing and Transwell assays, followed by in-vitro angiogenesis assay. One of the secretory factors mediating angiogenesis, leucine-rich α-2-glycoprotein-1 (LRG1), was measured in ovarian cancer cells. Signaling pathway mediating angiogenesis was further detected by western blotting. TUG1 was down-regulated in ovarian cancer cells by short hairpin RNA. Conditional medium originating from TUG1-knockdown cancer cells led to suppressed proliferation, migration, or invasion of endothelial cell line human umbilical vein endothelial cells. LRG1 expression and secretion was suppressed in ovarian cancer cells after TUG1 knockdown. Moreover, recombinant LRG1 rescued TUG1 knockdown-induced angiogenesis inhibition, and LRG1 probably mediated angiogenesis by tumor growth factor-β signaling pathway in endothelial cells. Long noncoding RNA-TUG1 mediates angiogenesis of endothelial cells by regulating LRG1 secretion from ovarian cancer cells partially through tumor growth factor-β pathway. Our results indicate the potency of TUG1 as a biomarker and therapeutic target for tumor-induced angiogenesis.

Pyrimethamine exerts significant antitumor effects on human ovarian cancer cells both in vitro and in vivo
imagePyrimethamine has been used principally to treat infections from protozoan parasites. Although previous studies have shown that pyrimethamine exhibited anticancer activity by inducing cellular apoptosis, there are none that show that pyrimethamine possesses anticancer activity with respect to ovarian cancer. We examined the roles of pyrimethamine on apoptosis and proliferation, DNA damage, and cell cycle distribution of human ovarian cancer cell lines in vitro. To investigate the antitumor efficacy of pyrimethamine in vivo, we established two intraperitoneal ovarian carcinoma models in nude mice. Pyrimethamine significantly induced apoptosis of ovarian cancer cells via growth inhibition, cell cycle arrest, and nuclear DNA damage in vitro and manifested antitumor activity by inhibiting tumor growth, thereby prolonging the survival time of tumor-bearing mice. We also demonstrated that pyrimethamine increased the expression of caspase-9 and decreased the expression of X-linked inhibitor of apoptosis protein. In conclusion, the antitumor effects of pyrimethamine were associated with enhanced apoptosis of tumor cells and inhibition of the growth of intratumoral microvessels. Our results indicate that pyrimethamine may provide an effective approach toward inhibiting the growth of ovarian cancer with minimal adverse effects.

MiR-29a inhibits cell proliferation and migration by targeting the CDC42/PAK1 signaling pathway in cervical cancer
imageCervical cancer is the second most common gynecological malignancy worldwide and the tumorigenesis mechanisms of cervical cancer are still unclear. This study aimed to reveal the role of miR-29a in cervical cancer. The expression level of miR-29a and CDC42 was measured using qRT-PCR. Cell proliferation, apoptosis, migration, and invasion were detected using colony formation, flow cytometry analysis, wound-healing assay, and Transwell assay, respectively. Luciferase reporter assay was used to determine the binding of miR-29a with CDC42. CDC42/p21-activated kinase 1 (PAK1) pathway-related proteins were measured by western blotting. MiR-29a was downregulated and CDC42 was upregulated in cervical cancer cells. Luciferase reporter assay showed that miR-29a negatively regulated the expression of CDC42 by directly targeting 3′-UTR of CDC42. Cell proliferation, migration, and invasion were markedly inhibited, whereas cell apoptosis was significantly increased in Hela and CaSki cells transfected with miR-29a mimics. These effects were partly recovered by CDC42 overexpression. Protein levels of PAK1, p-PAK1, p-LIMK, and p-cofilin were significantly downregulated by miR-29a mimics, which was reversed by CDC42 overexpression and was increased by the miR-29a inhibitor. MiR-29a inhibited cell proliferation, migration, and invasion, as well as promoted cell apoptosis through repressing the PAK1/LIMK signaling pathway by targeting CDC42 in cervical cancer.

Construction of an miRNA–mRNA regulatory network in colorectal cancer with bioinformatics methods
imageColorectal cancer (CRC) is the third most common cancer worldwide. This study aimed to explore the regulatory mechanisms of miRNAs in CRC. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in CRC tissue samples compared with control samples in mRNA and miRNA datasets were screened. Functional and pathway enrichment analysis of the DEGs was carried out. Targets of the DEMs were identified. Overlaps between the DEGs and targets of DEMs were selected. The miRNA–mRNA regulatory network of these overlaps was constructed and visualized. The candidate genes selected were validated by quantitative real-time PCR. DEGs were identified and considered DEGs-1 and DEGs-2. A total of 584 genes in DEGs-1 and 527 genes in DEGs-2 were obtained, including 465 overlaps, and 44 DEMs were identified. The overlaps were enriched in 46 Gene Ontology terms and 19 Kyoto Encyclopedia of Genes and Genomes pathways. Moreover, 137 overlapped genes between targets of the DEMs and the 465 overlaps were obtained. The miRNA–mRNA regulating network of the 137 overlapped genes was constructed. Extracellular matrix-related proteins and pathways might play critical roles in the development of CRC. The quantitative real-time PCR results of the candidates were in agreement with the bioinformatics analysis. miR-128, miR-182, and miR-143 might be key miRNAs regulating cell proliferation and metastasis of CRC.

Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer
imageEsophageal cancer (EC) is a common cancer worldwide. Sine oculis homeobox homolog (SIX3) is a human transcription factor that regulates the progression of vertebrate eye and fetal forebrain. However, studies on the function of SIX3 in human tumorigenesis remain rare. In this study, we aim to evaluate the role and the significance of SIX3 in EC. The TCGA database and clinical samples were used to assess the expression of SIX3 in EC patients. The Kaplan–Meier method and Cox's proportional hazards model were performed to analyze the correlations between SIX3 expression and EC clinical outcomes. The expressions of SIX3 in EC cells were measured by quantitative reverse transcription PCR analysis. The cell proliferation was detected using cell counting kit-8 and colony formation assay. The migration and invasion capacity of EC cells were evaluated using wound healing and Transwell methods. Western blot assay was used to measure the alterations in some important protein expression levels in the PI3K/Akt signaling pathway. We found that SIX3 was highly expressed in the EC tissues and cells. In addition, high expression of SIX3 was related to poor survival. The knockdown of SIX3 significantly inhibited the proliferation, migration, and invasion of ECA109 cells. A similar pattern was also found in the proliferation and migration of SKGT-4 cell line. The expression levels of some key proteins in the PI3K/Akt signaling pathway were obviously decreased after cells were transfected with si-SIX3, possibly resulting in PI3K/AKT signaling inactivation. In addition, E-cadherin and N-cadherin showed some change. Collectively, the results shed light on a potentially promoting role of SIX3 in human EC. Thus, SIX3 might be considered a novel prognostic biomarker and therapeutic target for EC patients.

Development of transferrin-modified poly(lactic-co-glycolic acid) nanoparticles for glioma therapy
imageGlioma is a primary intracranial malignant tumor with poor prognosis. In this study, we aimed to develop transferrin (Tf)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles to deliver temozolomide (TMZ) to glioma and evaluate their efficacy to kill glioma. TMZ-loaded nanoparticles were prepared by nanoprecipitation technique and targeted by Tf. Tf-PLGA-TMZ and PLGA-TMZ were characterized for average particle sizes and zeta potentials, cellular uptake and cytotoxicity as well as in-vitro drug release of these nanoparticles were evaluated in human glioma U87MG cells. In-vivo antiglioma efficacy of Tf-PLGA-TMZ was evaluated in nude mice. Polydispersity ratio increased from 0.132 to 0.150, while encapsulation efficiency decreased from 69.4 to 55.8% after Tf modification of PLGA-TMZ. High performance liquid chromatography test showed that Tf-targeted nanoparticles were better internalized into U87MG cells than nontargeted nanoparticles. Moreover, Tf-PLGA-TMZ significantly decreased the viability of U87MG cells compared with nontargeted nanoparticles (P<0.05). In addition, Tf-PLGA-TMZ significantly decreased tumor volume and improved the survival of nude mice injected with U87MG cells. Tf-modified PLGA nanoparticles could be used for effective delivery of TMZ and have promise for the treatment of glioma.

Evodiamine inhibits migration and invasion by Sirt1-mediated post-translational modulations in colorectal cancer
imageColorectal cancer (CRC) is one of the most difficult cancers to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidences show that Evodiamine (EVO) exerts an inhibitory effect on cancer cell apoptosis, migration, and invasion. In this study, we investigated the effects of EVO on the metastasis of CRC cells in vitro and in vivo. In vitro, wound-healing and transwell assay showed that migration and invasion of HT-29 and HCT-116 CRC cells were inhibited significantly by EVO. Western blot and RT-PCR showed that EVO reduced the expression of matrix metalloproteinase-9 in a dose-dependent manner. In EVO-induced cells, the intracellular NAD+/NADH ratio was increased, the level of Sirt1 was increased, and acetyl-NF-κB P65 was decreased. This process was inhibited by nicotinamide, an inhibitor of Sirt1. In vivo, EVO reduced tumor metastasis markedly. These findings provide evidences that EVO suppresses the migration and invasion of CRC cells by inhibiting the acetyl-NF-κB p65 by Sirt1, resulting in suppression of metalloproteinase-9 expression in vitro and in vivo.

Novel small molecule decreases cell proliferation, migration, clone formation, and gene expression through ERK inhibition in MCF-7 and MDA-MB-231 breast cancer cell lines
imageThe Ras–Raf–MEK1/2–ERK1/2 pathway is an attractive target for the development of anticancer agents because of the high prevalence of ERK activation in human cancers. However, resistance is often developed despite initial clinical response, most likely because of activation of cross-talk pathways. In Research Genetic Cancer Center (RGCC), we are in the process of synthesizing a novel ERK inhibitor, targeting the final stage of the pathway, thus minimizing cross-talk. We have synthesized an intermediate molecule –RGCC416 – and tested its biological activity. MCF-7 and MDA-MB-231 cells were used. Cell viability was measured by crystal violet and cell proliferation by the methyl tetrazolium assay using various compound concentrations. Cell migration and colony formation were determined to assess the ability of invasion and single cancer cell growth, respectively. Expression of genes linked to MAPK/PI3K pathways was determined by PCR. ERK and phospho-ERK levels were determined in both the cytoplasm and the nucleus by western blot. It was found that although the compound did not affect viability, it significantly decreased cell proliferation, migration, and colony formation in both cell lines. In MDA-MB-231, this is possibly through retaining phospho-ERK to the cytoplasm, where it cannot activate cancer-associated genes. There was no difference in ERK levels in MCF-7 cells. This could be because of the different pathways that these cells utilize for survival. We have synthesized a molecule, which could be a promising ERK inhibitor, leading to possible novel treatment options for breast cancer patients.



Clinical Reports
 
 
 

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution
Maximilian Hochmair, Christoph Weinlinger, Sophia Schwab, Jakob Naber, Ulrike Setinek, Dagmar Krenbek, Matthias H. Urban, Hannah Fabikan, Stefan Watzka, Renate Koger, Andreas Fazekas, Erwin Bitterlich, Arschang Valipour, Otto C. Burghuber

Poor outcome for patients with gastric cancer and lung metastases treated with ramucirumab and paclitaxel
Giandomenico Roviello, Silvia P. Corona, Andrea G. Multari, Roberto Petrioli, Pietro Rosellini, Michele Aieta

 
Case Reports
 
 
 

Misleading impaired liver function in a non-small-cell lung cancer patient treated with pembrolizumab: a case report
Giorgia A. Osman, Arnaldo Marra, Daniela Iacono, Valerio Giannelli, Serena Ricciardi, Daniele Remotti, Andrea Vecchione, Alberto Ricci, Paolo Palange, Maria R. Migliorino

Apatinib, combined with chemotherapy or alone is effective in treating angiosarcoma: a case report
Mingyang Liu, Yongmin Liu, Huannan Guo, Dongwei Fu, Lili Lv, Chunhong Chen, Yanlin Li, Wenqian Zhang, Ming Yao, Limin Zhao



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

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