Repurposing of posaconazole as a hedgehog/SMO signaling inhibitor for embryonal rhabdomyosarcoma therapy

xlomafota13 shared this article with you from Inoreader Repurposing of posaconazole as a hedgehog/SMO signaling inhibitor for embryonal rhabdomyosarcoma therapy Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4528-4540. eCollection 2021. ABSTRACT Posaconazole (POS) is a novel antifungal agent, which has been repurposed as an anti-tumor drug for its potential inhibition of Hedgehog signaling pathway. Hedgehog pathway is reported to be abnormally activated in embryonal rhabdomyosarcoma (ERMS), this study aimed to reveal whether POS could inhibit Hedgehog signaling pathway in ERMS. Following POS treatment, XTT viability assay was used to determine the cell proliferation of ERMS cell lines. Protein changes related to Hedgehog signaling, cell cycle and autophagy were detected by Western blot. The cell cycle distribution was analyzed by flow cytometry. Moreover, a subcutaneous tumor mouse model of ERMS was established to assess the anti-tumor effect of POS. POS was found to inhibit tumor progression by inducing G0/G1 arrest and autophagy of RD, RMS-YM, and KYM-1 cells dose-dependently. Western blot demonstrated that POS downregulated the expressions of SMO, Gli1, c-Myc, CDK4, and CDK6, while upregulated the expressions of autophagy-related proteins. Immunofluorescence microscopy revealed a significant increase of LC3B puncta in POS-treated ERMS cells. Furthermore, POS treatment led to a significant inhibition of tumor growth in mice bearing ERMS. Our findings could provide a theoretical basis and have important clinical implications in developing POS as a promising agent against ERMS by targeting Hedgehog pathway. PMID:34659903 | PMC:PMC8493378 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Current methodologies to detect circulating tumor cells: a focus on ovarian cancer

xlomafota13 shared this article with you from Inoreader Current methodologies to detect circulating tumor cells: a focus on ovarian cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4111-4126. eCollection 2021. ABSTRACT Identification of circulating tumor cells (CTC) in liquid biopsies opens a window of opportunities for the optimization of clinical management of oncologic patients. In ovarian cancer (OC), which involves atypical routes of metastatic spread, CTC analyses may also offer novel insights about the mechanisms behind malignant progression of the disease. However, current methodologies struggle to precisely define CTC number in the peripheral blood of OC patients, and the isolation of viable cells for further characterization is still challenging. The biggest limitation is the lack of methodological standardization for OC CTC detection, preventing comprehensive definition of their clinical potential required for the transfer to practice. Here we describe and compare methods for CTC analysis that have been implemented for OC thus far, discussing pros, cons and improvemen ts needed. We identify biophysical separation approaches as optimal for CTC enrichment. On the other hand, the identification of specific tumor antigens or gene transcripts, despite displaying drawbacks related to tumor heterogeneity, still remains the best approach for OC CTC detection. PMID:34659879 | PMC:PMC8493391 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Anti-cancer effects of Hederoside C, a pentacyclic triterpene saponin, through the intrinsic apoptosis and STAT3 signaling pathways in osteosarcoma

xlomafota13 shared this article with you from Inoreader Anti-cancer effects of Hederoside C, a pentacyclic triterpene saponin, through the intrinsic apoptosis and STAT3 signaling pathways in osteosarcoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4541-4550. eCollection 2021. ABSTRACT Natural compounds have emerged as an approach in cancer therapy. Pulsatilla koreana Nakai is used as a traditional medicinal plant that found throughout China and Korea. However, anti-cancer effects of Hederoside C (HedC) isolated from P. koreana has not been investigated in osteosarcoma. The present study aimed to demonstrate anti-cancer functions of HedC against human osteosarcoma cells. Herein, we found that HedC suppressed the proliferation of MG63 cells and U2OS cells in the dose- and time-dependent manner, and caused intrinsic apoptosis pathways as evidenced by morphological changes, TUNEL-positive cells, cleaved-PARP, and cleaved-caspase 9 and 3. HedC increased p53, Bax, and p21, whereas HedC reduced Bcl-2. HedC-mediated apoptosis was accompanied by decreases in the mitogen-activated protein kinases (MAPKs) and STAT3 phosphorylation. Wound hea ling and Boyden chamber assays also showed the anti-metastatic effects of HedC by suppressing migration and invasion. In addition, the anti-cancer effects of HedC were observed in in vivo xenograft mice model, and HedC treatment induced the decreased PCNA and p-STAT3 as well as the increased p53 and cleaved caspase-3. Taken together, our results provide evidence that HedC might be an attractive therapeutic strategy against osteosarcoma. PMID:34659904 | PMC:PMC8493407 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells

xlomafota13 shared this article with you from Inoreader Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4199-4219. eCollection 2021. ABSTRACT Although considered a sporadic type of skin cancer, malignant melanoma has regularly increased internationally and is a major cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effect of capsaicin on melanoma growth. The cellular thermal shift assay (CETSA), isothermal dose-response fingerprint curves (ITDRFCETSA), and CETSA-pulse proteolysis were utilized to confirm the direct binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analy sis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice. Our data show that capsaicin directly engaged with cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin was accompanied by the attenuation of SIRT1, a NAD+-dependent deacetylase. The suppression of tNOX and SIRT1 then enhanced ULK1 acetylation and induced ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Taken together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting ROS-dependent autophagy in melanoma cells. PMID :34659883 | PMC:PMC8493390 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genomic alterations in tumor tissue and ctDNA from Chinese pancreatic cancer patients

xlomafota13 shared this article with you from Inoreader Genomic alterations in tumor tissue and ctDNA from Chinese pancreatic cancer patients Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4551-4567. eCollection 2021. ABSTRACT Though the genomic feature of pancreatic cancer has been comprehensively studied in western patients, the genetic feature of Chinese patients is poorly clarified. In this study, a total of 225 pancreatic cancer patients were enrolled, mainly pancreatic ductal adenocarcinoma (PDAC, 97.33%). 140 patients (62.22%) provided sufficient tumor tissues for genomic analysis, and the rest (37.78%) were provided serum instead. Utilizing target next-generation sequencing (NGS), we analyzed genomic alterations of 618 selected genes. Corresponding data in the TCGA database were also analyzed here. In total, 26 (11.61%) patients had pathogenic or likely pathogenic germline variants, mainly (84.62%) involved genes in the DNA damage repair (DDR) pathway. The mean and median counts of somatic alterations per sample were 6.28 and 5, respectively. The most frequently mutated genes in our cohort were KRAS, TP53, CDKN2A, SMAD4, FBXW7 and ARID1A, revealing a significantly different prevalence of genes including KRAS, CDKN2A, ARID1A, NOTCH1, ARID1B than the corresponding data in the TCGA database. 39.11% of patients were identified with actionable alteration and the ratio was not significantly different between tissue and serum samples. 22.67% of patients harbored DDR gene alterations, which were associated with a higher tumor mutation burden. We also found that all the DDR alterations were not correlated with the overall survival and immune and stroma score, but the changes in NK cells and follicular T cells were identified in samples with DDR changes according to TCGA database. In summary, we identified a distinct genomic feature of Chinese pancreatic cancer patients by comparing with the data in TCGA database, and suggested the role for genetic testing using tissue or ctDNA samples in decision-making process. DDR alterations were associated with a higher tumor mutation burden and the significantly higher counts of NK cells in DDR altered samples may raise the attention in future related drugs development. PMID:34659905 | PMC:PMC8493393 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Serine/threonine-protein kinase 24 is an inhibitor of gastric cancer metastasis through suppressing CDH1 gene and enhancing stemness

xlomafota13 shared this article with you from Inoreader Serine/threonine-protein kinase 24 is an inhibitor of gastric cancer metastasis through suppressing CDH1 gene and enhancing stemness Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4277-4293. eCollection 2021. ABSTRACT Gastric cancer patients often present with distant metastasis and advanced stages. Suppressing serine/threonine-protein kinase 24 (STK24, also known as MST3) is known to promote gastric tumorigenesis. Here, we investigated the effects from STK24 on the metastasis of gastric cancer. We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology for genetic knockout of STK24 at the genomic DNA level in human MKN45 and mouse M12 gastric cancer cells. To assess the consequences of STK24 knockdown, western blot, cell migration, and wound healing assays were conducted in vitro. An in vivo mouse model of liver metastasis was established and tested, and bioinformatics analyses were performed. The knockdown of the STK24 gene enhanced cell migration and increased liver metastasis in the mouse model of gastric ca ncer. STK24-silenced tumors suppressed CD4+ T cells and enhanced the expansion of CD11b+Ly6C+ myeloid-derived suppressor cells (MDSCs) and F4/80+ macrophages in the spleen of the mice. In MKN45 cells, STK24 silencing resulted in downregulation of E-cadherin (gene CDH1, Cadherin-1, or epithelial cadherin). In 38 paired specimens of gastric adenocarcinomas and normal tissues, we examined STK24 and CDH1 expression levels via western blot; a positive correlation between the expression levels of STK24 and CDH1 was found (R2 = 0.5507, P = 9.72 × 10-8). Furthermore, in Oncomine database and Kaplan-Meier plotter analysis, the loss of CDH1, increase in CCL2, and upregulation of CD44 were correlated with poor prognosis of gastric cancer patients. Our results demonstrate that knockdown of STK24 increases cell migration through suppressing CDH1 and enhancing CD44. In experimental model of metastatic gastric cancer in syngeneic inbred mice, STK24 is important for immune suppression through expansion of CD11b+Ly6C+ MDSCs and F4/80+ macrophages. We confirmed that STK24 is an inhibitor of gastric cancer metastasis. PMID:34659887 | PMC:PMC8493374 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Effect of APOBEC3A functional polymorphism on renal cell carcinoma is influenced by tumor necrosis factor-α and transcriptional repressor ETS1

xlomafota13 shared this article with you from Inoreader Effect of <em>APOBEC3A</em> functional polymorphism on renal cell carcinoma is influenced by tumor necrosis factor-α and transcriptional repressor ETS1 Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4347-4363. eCollection 2021. ABSTRACT Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) 3 cytidine deaminases are the prominent drivers of somatic mutations in cancers. However, the effect of APOBEC3s functional polymorphisms on the development of renal cell carcinoma (RCC) remains unknown. Five genetic polymorphisms affecting the expression of APOBEC3A (A3A), APOBEC3B, and APOBEC4 and uracil DNA glycosylase (UNG) were genotyped in 728 RCC patients and 1500 healthy controls. The effects of tumor necrosis factor-α (TNFα) and interleukin-6 on the activity of the A3A promoter with rs12157810-A or -C in four RCC cell lines (786-O, A498, Caki2, ACHN) and two colorectal cancer cell lines (HCT116, SW620) were evaluated using dual-luciferase assays. Transcriptional repressors to the A3A promoter were identified by chromatin immunoprecipitation-quantitative PCR. The proapoptotic effect of A3A on RCC cells was evaluated using cytometry. The prognostic values of A3A and ETS1 were evaluated by the Cox regression analysis. The expressions of A3A and ETS1 were evaluated in clear cell RCC (ccRCC) specimens with different polymorphic genotypes using quantitative RT-PCR and immunohistochemistry. Of those functional polymorphisms, CC genotype at rs12157810 in the A3A promoter was significantly associated with a decreased risk of ccRCC, compared to the AA genotype (odds ratio adjusted for age and gender, 0.41, 95% confidence interval [CI], 0.28-0.57). Other polymorphic genotypes were not associated with the risk of RCC. The activity of the A3A promoter with rs12157810-C was significantly higher than that with rs12157810-A in the four RCC cell lines and two colorectal cancer cell lines. The activity of the A3A promoter with rs12157810-C was greatly up-regulated by TNFα and predominantly inhibited by a transcriptional repre ssor ETS1. The binding of ETS1 to the A3A promoter with rs12157810-C was looser than that with rs12157810-A. Ectopic expression of A3A significantly promoted apoptosis in ccRCC cells, rather than in colorectal cancer cells. Higher ETS1 expression predicted a favorable prognosis in ccRCC, with a hazard ratio of 0.58 (95% CI, 0.43-0.78). Rs121567810-C up-regulates the A3A promoter activity, possibly due to higher response to TNFα and looser transcriptional repression by ETS1. Up-regulation of A3A increases apoptosis, thus decreasing ccRCC risk in those carrying rs121567810-C. PMID:34659891 | PMC:PMC8493372 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Tumor-treating fields as a proton beam-sensitizer for glioblastoma therapy

xlomafota13 shared this article with you from Inoreader Tumor-treating fields as a proton beam-sensitizer for glioblastoma therapy Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4582-4594. eCollection 2021. ABSTRACT Few advances in GBM treatment have been made since the initiation of the Stupp trials in 2005. Experimental studies on immunotherapy drugs, molecular inhibitors, radiation dosage escalation and vascular growth factor blockers have all failed to provide satisfactory outcomes. TTFields therapy, on the other hand, have emerged as a viable substitute to therapies like radiation in GBM patients having a highly immunosuppressive tumor microenvironment. To enhance the biofunctional impacts, we explored the combination events with TTFields and proton treatment in this study. We conducted a cell viability test, a cell death detection evaluation, a ROS analysis, a three-dimensional (3D) culture system, and a migration assay. The combination of proton radiation and TTFields therapy laid a substantial anticancer impact on the F98 and U373 as compared to the consequences of ei ther of these therapies used separately. The combination proton beam therapy used by TTFields was very successful in curbing GBM from migrating. GBM cell metastasis is restricted by TTFields combined proton by downregulating the MAPK, NF-κB, and PI3K/AKT indicating pathways, caused by reduced EMT marker expression. These findings furnish biological proof for the molecular grounds of TTFields in combination with proton used for GBM therapy. PMID:34659907 | PMC:PMC8493382< /p> View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Subclinical doxorubicin-induced cardiotoxicity update: role of neutrophils and endothelium

xlomafota13 shared this article with you from Inoreader Subclinical doxorubicin-induced cardiotoxicity update: role of neutrophils and endothelium Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4070-4091. eCollection 2021. ABSTRACT Doxorubicin (DOX) is a highly effective chemotherapy agent that often causes cardiotoxicity. Despite a number of extensive studies, the risk for DOX cardiotoxicity remains unpredictable. The majority of the studies on DOX-induced cardiotoxicity have been focused on the effects on cardiomyocytes that lead to contractile dysfunction. The roles of systemic inflammation, endothelial injury and neutrophil recruitment, all induced by the DOX, are increasingly recognized as the mechanisms that trigger the development and progression of DOX-induced cardiomyopathy. This review explores recent data regarding the possible mechanisms and biomarkers of early subclinical DOX-associated cardiotoxicity. PMID:34659877 | PMC:PMC8493405 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Preferred method of therapy for patients with early-stage high-grade neuroendocrine carcinoma of the cervix

xlomafota13 shared this article with you from Inoreader Preferred method of therapy for patients with early-stage high-grade neuroendocrine carcinoma of the cervix Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4595-4606. eCollection 2021. ABSTRACT High-grade neuroendocrine carcinoma of the uterine cervix (HGNECC) is a rare and overly aggressive malignancy. Due to its rarity, there is no standard treatment. A majority of early-stage patients receive radical hysterectomy and lymph node dissection (RH+LND), followed by adjuvant chemotherapy. To explore the most suitable methods of therapy, a multicenter retrospective review of HGNECC patients was conducted. A total of 133 patients (I-IIA, FIGO 2009) treated from March 2003 to September 2018 were enrolled in this study. The 5-year DFS and OS rates for stages IB and IIA were 44.8% and 39.5%, and 53.8% and 39.6%, respectively. The median DFS and OS for stages IB and IIA were 41 months and 12 months, and 63 months and 45 months, respectively. The RH+LND surgery procedure was associated with a significantly better DFS (P=0.015) and OS (P=0.006), while the bilateral salpingo-oophorectomy (BSOE) was also associated with a better OS (P=0.023). The efficacy of paclitaxel-platinum (TP/C) adjuvant chemotherapy regimens need to be confirmed using clinical trials, especially for tumors with a diameter of >4 cm (P=0.0005). Therefore, the RH+LND+BSOE procedure was recommended for HGNECC patients at stages IB-IIA. TP/C is an alternative chemotherapy regimen that results in optimal survival. Moreover, a tumor diameter of >4 cm, LNM, DSI, and LVSI were confirmed as high-risk factors for worse DFS and OS. Patients without risk factor, 1 or 2 or 3 risk factors, and 4 risk factors had significantly different DFS and OS values. PMID:34659908 | PMC:PMC8493402 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cyy260, a novel small molecule inhibitor, suppresses non-small cell lung cancer cell growth via JAK2/STAT3 pathway

xlomafota13 shared this article with you from Inoreader Cyy260, a novel small molecule inhibitor, suppresses non-small cell lung cancer cell growth via JAK2/STAT3 pathway Via American Journal of Cancer Research Am J Cancer Res. 2021 Sep 15;11(9):4241-4258. eCollection 2021. ABSTRACT Non-small cell lung cancer (NSCLC) is a malignant tumor that accounts for the most new cancer cases and cancer-related deaths worldwide, and the proliferation and metastasis of NSCLC are the main reasons for treatment failure and patient death. Traditional chemotherapeutic drugs have low selectivity, which can kill cancer cells and cause damage to normal cells at the same time. Therefore, it is particularly important to study therapies that target cancer cells and to find low-toxicity, high-efficiency anticancer drugs. Cyy260 is a novel small molecule inhibitor that we synthesized for the first time. Here, we investigated the in vitro and in vivo antitumor activities of Cyy260 and explored the underlying mechanisms in NSCLC. Cyy260 had a concentration- and time-dependent inhibitory effect on NSCLC cells, but it was less toxic to normal cells. Cyy260 regulated apoptosis through intracellular and extracellular apoptotic pathways. In addition, Cyy260 could also induce cell cycle arrest, thereby inhibiting cell proliferation. Further analysis of molecular mechanisms showed that the JAK2/STAT3 signaling pathway was involved in the antitumor effect mediated by Cyy260. Analysis of subcutaneously transplanted tumors in mice showed that Cyy260 suppressed tumor growth in vivo. Our results proved that Cyy260 is a novel inhibitor of the JAK2/STAT3 pathway thus may have potential in therapy of NSCLC and other cancers. PMID:34659885 | PMC:PMC8493399 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.