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Melanoma: HELP
Articles by Gregory B. Lesinski
Based on 17 articles published since 2009
(Why 17 articles?)

Between 2009 and 2019, G. B. Lesinski wrote the following 17 articles about Melanoma.
+ Citations + Abstracts
1 Editorial The potential for targeting the STAT3 pathway as a novel therapy for melanoma. 2013

Lesinski, Gregory B. · ·Future Oncol · Pubmed #23837753.

ABSTRACT: -- No abstract --

2 Review Immunomodulatory cytokines as therapeutic agents for melanoma. 2011

Nicholas, Courtney / Lesinski, Gregory B. ·The Ohio State University, Department of Internal Medicine, Division of Medical Oncology, Columbus, OH 43210, USA. ·Immunotherapy · Pubmed #21554095.

ABSTRACT: Melanoma is the most aggressive form of skin cancer whose worldwide incidence is rising faster than any other cancer. Few treatment options are available to patients with metastatic disease, and standard chemotherapeutic agents are generally ineffective. Cytokines such as IFN-α or IL-2 can promote immune recognition of melanoma, occasionally inducing dramatic and durable clinical responses. Here, we discuss several immunomodulatory agents, the safety of which are being evaluated in clinical trials. Challenges include an incomplete understanding of signaling pathways, appropriate clinical dose and route, and systemic immunosuppression in advanced melanoma patients. We consider how targeted cytokine therapy will integrate into the clinical arena, as well as the low likelihood of success of single cytokine therapies. Evidence supports a synergy between cytokine immunotherapy and other therapeutic approaches in melanoma, and strengthening this area of research will improve our understanding of how to use cytokine therapy better.

3 Clinical Trial A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma. 2014

Monk, Paul / Lam, Elaine / Mortazavi, Amir / Kendra, Kari / Lesinski, Gregory B / Mace, Thomas A / Geyer, Susan / Carson, William E / Tahiri, Sanaa / Bhinder, Arvinder / Clinton, Steven K / Olencki, Thomas. ·*Division of Medical Oncology, Comprehensive Cancer Center, The Ohio State University, and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH †Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver, CO. ·J Immunother · Pubmed #24598448.

ABSTRACT: This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h × 8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.

4 Clinical Trial A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma. 2014

Markowitz, Joseph / Luedke, Eric A / Grignol, Valerie P / Hade, Erinn M / Paul, Bonnie K / Mundy-Bosse, Bethany L / Brooks, Taylor R / Dao, Thao-Vi / Kondalasula, Sri V / Lesinski, Gregory B / Olencki, Thomas / Kendra, Kari L / Carson, William E. ·Divisions of *Medical Oncology †Surgical Oncology ‡Center for Biostatistics, The Ohio State University, Columbus, OH. ·J Immunother · Pubmed #24316557.

ABSTRACT: The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

5 Article The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors. 2017

Farren, Matthew R / Hennessey, Rebecca C / Shakya, Reena / Elnaggar, Omar / Young, Gregory / Kendra, Kari / Landesman, Yosef / Elloul, Sivan / Crochiere, Marsha / Klebanov, Boris / Kashyap, Trinayan / Burd, Christin E / Lesinski, Gregory B. ·Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. · Department of Molecular Genetics, The Ohio State University, Columbus, Ohio. · Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio. · Target Validation Shared Resource, The Ohio State University, Columbus, Ohio. · Division of Internal Medicine, The Ohio State University, Columbus, Ohio. · Center for Biostatistics, The Ohio State University, Columbus, Ohio. · Karyopharm Therapeutics, Newton, Massachusetts. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. gregory.b.lesinski@emory.edu. ·Mol Cancer Ther · Pubmed #28148715.

ABSTRACT: Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth

6 Article Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. 2014

Yang, Jennifer / Bill, Matthew A / Young, Gregory S / La Perle, Krista / Landesman, Yosef / Shacham, Sharon / Kauffman, Michael / Senapedis, William / Kashyap, Trinayan / Saint-Martin, Jean-Richard / Kendra, Kari / Lesinski, Gregory B. ·Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. · Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America. · Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America. · Karyopharm Therapeutics, Natick, Massachusetts, United States of America. ·PLoS One · Pubmed #25057921.

ABSTRACT: XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.

7 Article PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.). 2013

Nicholas, Courtney / Yang, Jennifer / Peters, Sara B / Bill, Matthew A / Baiocchi, Robert A / Yan, Fengting / Sïf, Saïd / Tae, Sookil / Gaudio, Eugenio / Wu, Xin / Grever, Michael R / Young, Gregory S / Lesinski, Gregory B. ·Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America. ·PLoS One · Pubmed #24098663.

ABSTRACT: Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.

8 Article Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines. 2012

Bill, Matthew A / Nicholas, Courtney / Mace, Thomas A / Etter, Jonathan P / Li, Chenglong / Schwartz, Eric B / Fuchs, James R / Young, Gregory S / Lin, Li / Lin, Jiayuh / He, Lei / Phelps, Mitch / Li, Pui-Kai / Lesinski, Gregory B. ·Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. ·PLoS One · Pubmed #22899991.

ABSTRACT: The Janus kinase-2 (Jak2)-signal transducer and activator of transcription-3 (STAT3) pathway is critical for promoting an oncogenic and metastatic phenotype in several types of cancer including renal cell carcinoma (RCC) and melanoma. This study describes two small molecule inhibitors of the Jak2-STAT3 pathway, FLLL32 and its more soluble analog, FLLL62. These compounds are structurally distinct curcumin analogs that bind selectively to the SH2 domain of STAT3 to inhibit its phosphorylation and dimerization. We hypothesized that FLLL32 and FLLL62 would induce apoptosis in RCC and melanoma cells and display specificity for the Jak2-STAT3 pathway. FLLL32 and FLLL62 could inhibit STAT3 dimerization in vitro. These compounds reduced basal STAT3 phosphorylation (pSTAT3), and induced apoptosis in four separate human RCC cell lines and in human melanoma cell lines as determined by Annexin V/PI staining. Apoptosis was also confirmed by immunoblot analysis of caspase-3 processing and PARP cleavage. Pre-treatment of RCC and melanoma cell lines with FLLL32/62 did not inhibit IFN-γ-induced pSTAT1. In contrast to FLLL32, curcumin and FLLL62 reduced downstream STAT1-mediated gene expression of IRF1 as determined by Real Time PCR. FLLL32 and FLLL62 significantly reduced secretion of VEGF from RCC cell lines in a dose-dependent manner as determined by ELISA. Finally, each of these compounds inhibited in vitro generation of myeloid-derived suppressor cells. These data support further investigation of FLLL32 and FLLL62 as lead compounds for STAT3 inhibition in RCC and melanoma.

9 Article β-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. 2011

Lemeshow, Stanley / Sørensen, Henrik Toft / Phillips, Gary / Yang, Eric V / Antonsen, Sussie / Riis, Anders H / Lesinski, Gregory B / Jackson, Rebecca / Glaser, Ronald. ·College of Public Health, The Ohio State University Medical Center, Columbus, OH 43210, USA. ·Cancer Epidemiol Biomarkers Prev · Pubmed #21933972.

ABSTRACT: BACKGROUND: To study whether use of β-blockers increases survival in patients with malignant melanoma because experimental data suggest that catecholamine hormones may be involved in stimulating the aggressiveness of malignant melanoma. METHODS: A total of 4,179 patients diagnosed with malignant melanoma in Denmark with a median follow-up of 4.9 years and identified in the Danish Cancer Registry participated. Data on β-blocker use, comorbidity, and survival were obtained from medical and administrative databases. Cox proportional hazards models were used to estimate HRs for all-cause mortality with 95% CIs with adjustment for prognostic factors. RESULTS: A total of 372 (8.9%) patients with malignant melanoma were treated with β-blockers within 90 days of melanoma diagnosis. The median β-blocker duration for exposure within 90 days of melanoma diagnosis, more than 90 days, and no prior exposure was 7.6, 1.4, and 0 years, respectively. The patients receiving β-blockers were older, had more comorbidities, and more cardiovascular and psychotropic drug user than the patients receiving no β-blockers prior to melanoma diagnosis. After adjustment for age and comorbidity index, the HR for melanoma death was 0.87 (95% CI: 0.64-1.20) and for all-cause mortality was 0.81 (95% CI: 0.67-0.97). CONCLUSION: Increased survival time of patients with melanoma receiving β-blockers suggests that this class of drugs may hold promise in treatment strategy for these patients. IMPACT: The observations described here suggest that catecholamines may retard melanoma progression and that β-blockers may have unrecognized potential as a therapeutic intervention for melanoma.

10 Article miR-21 and miR-155 are associated with mitotic activity and lesion depth of borderline melanocytic lesions. 2011

Grignol, V / Fairchild, E T / Zimmerer, J M / Lesinski, G B / Walker, M J / Magro, C M / Kacher, J E / Karpa, V I / Clark, J / Nuovo, G / Lehman, A / Volinia, S / Agnese, D M / Croce, C M / Carson, W E. ·Department of Surgery, The Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210, USA. ·Br J Cancer · Pubmed #21863027.

ABSTRACT: BACKGROUND: Expression of microRNAs (miRs) has been shown to be altered in many solid tumours and is being explored in melanoma. The malignant potential of some melanocytic lesions is difficult to predict. We hypothesised that characterisation of miR expression in borderline melanocytic proliferations would lead to the identification of a molecular profile that could be used with known prognostic factors to differentiate lesions with high malignant potential. METHODS: The miR expression profile of melanocytic lesions (benign naevi, malignant melanoma and borderline melanocytic tumours) was evaluated by real-time PCR. RESULTS: PCR analysis revealed primary cutaneous melanomas had an 8.6-fold overexpression of miR-21 and a 7.5-fold overexpression of miR-155 compared with benign naevi (P<0.0001). In situ hybridisation confirmed these results. miR-21 and miR-155 were significantly overexpressed within borderline lesions (P=0.0011 and P=0.0048, respectively). When borderline lesions were categorised by mitotic activity and Breslow thickness, miR-21 was associated with mitotic activity and miR-155 was associated with thickness (P<0.025). Among 14 patients with borderline lesions who underwent sentinel lymph node biopsy (SLNB), positive SLNB was associated with increased miR-21 and miR-155 in the primary lesion compared with lesions with a negative SLNB. CONCLUSION: MicroRNA expression profiles can be used to characterise atypical melanocytic lesions.

11 Article Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4⁺ and CD8⁺ T cells. 2011

Guenterberg, Kristan D / Lesinski, Gregory B / Mundy-Bosse, Bethany L / Karpa, Volodymyr I / Jaime-Ramirez, Alena Cristina / Wei, Lai / Carson, William E. ·Department of Surgery, Columbus, OH 3210, Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, N924 Doan Hall 410 W. 10th Ave, Columbus, OH 43210, USA. ·Cancer Immunol Immunother · Pubmed #21604070.

ABSTRACT: Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1(-/-)) or control (SOCS1(+/+)) mice on an IFN-γ(-/-) C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1(+/+) mice receiving IFN-A/D had significantly enhanced survival versus PBS-treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1(-/-) mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1(-/-) mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8(+) T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1(-/-) mice as compared with mice receiving a control antibody (P = 0.0021). CD4(+) T-cell depletion from SOCS1(-/-) mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1(+/+) or SOCS1(-/-) mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1(+/+) or SOCS1(-/-) mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor effects of IFN-α in the setting of melanoma.

12 Article Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment. 2011

He, Hongyan / Grignol, Valerie / Karpa, Volodymyr / Yen, Chi / LaPerle, Krista / Zhang, Xiaoli / Jones, Natalie B / Liang, Margaret I / Lesinski, Gregory B / Ho, W S Winston / Carson, William E / Lee, L James. ·Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, OH, USA. ·J Control Release · Pubmed #21362447.

ABSTRACT: The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform.

13 Article The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. 2010

Bill, Matthew A / Fuchs, James R / Li, Chenglong / Yui, Jennifer / Bakan, Courtney / Benson, Don M / Schwartz, Eric B / Abdelhamid, Dalia / Lin, Jiayuh / Hoyt, Dale G / Fossey, Stacey L / Young, Gregory S / Carson, William E / Li, Pui-Kai / Lesinski, Gregory B. ·Department of Surgery, Arthur G, James Cancer Hospital and Richard J, Solove Research Institute, The Ohio State University, 410 W, 10th Ave, Columbus, OH 43210, USA. ·Mol Cancer · Pubmed #20576164.

ABSTRACT: BACKGROUND: We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. RESULTS: FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-gamma-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-gamma, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-gamma production when cultured with K562 targets as compared to vehicle (DMSO). CONCLUSIONS: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.

14 Article Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells. 2010

Lesinski, Gregory B / Zimmerer, Jason M / Kreiner, Melanie / Trefry, John / Bill, Matthew A / Young, Gregory S / Becknell, Brian / Carson, William E. ·Department of Surgery Arthur G, James Cancer Hospital and Richard J, Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. ·BMC Cancer · Pubmed #20398276.

ABSTRACT: BACKGROUND: Endogenously produced interferons can regulate the growth of melanoma cells and are administered exogenously as therapeutic agents to patients with advanced cancer. We investigated the role of negative regulators of interferon signaling known as suppressors of cytokine signaling (SOCS) in mediating interferon-resistance in human melanoma cells. METHODS: Basal and interferon-alpha (IFN-alpha) or interferon-gamma (IFN-gamma)-induced expression of SOCS1 and SOCS3 proteins was evaluated by immunoblot analysis in a panel of n = 10 metastatic human melanoma cell lines, in human embryonic melanocytes (HEM), and radial or vertical growth phase melanoma cells. Over-expression of SOCS1 and SOCS3 proteins in melanoma cells was achieved using the PINCO retroviral vector, while siRNA were used to inhibit SOCS1 and SOCS3 expression. Tyr701-phosphorylated STAT1 (P-STAT1) was measured by intracellular flow cytometry and IFN-stimulated gene expression was measured by Real Time PCR. RESULTS: SOCS1 and SOCS3 proteins were expressed at basal levels in melanocytes and in all melanoma cell lines examined. Expression of the SOCS1 and SOCS3 proteins was also enhanced following stimulation of a subset of cell lines with IFN-alpha or IFN-gamma. Over-expression of SOCS proteins in melanoma cell lines led to significant inhibition of Tyr701-phosphorylated STAT1 (P-STAT1) and gene expression following stimulation with IFN-alpha (IFIT2, OAS-1, ISG-15) or IFN-gamma (IRF1). Conversely, siRNA inhibition of SOCS1 and SOCS3 expression in melanoma cells enhanced their responsiveness to interferon stimulation. CONCLUSIONS: These data demonstrate that SOCS proteins are expressed in human melanoma cell lines and their modulation can influence the responsiveness of melanoma cells to IFN-alpha and IFN-gamma.

15 Article Interleukin-29 binds to melanoma cells inducing Jak-STAT signal transduction and apoptosis. 2010

Guenterberg, Kristan D / Grignol, Valerie P / Raig, Ene T / Zimmerer, Jason M / Chan, Anthony N / Blaskovits, Farriss M / Young, Gregory S / Nuovo, Gerard J / Mundy, Bethany L / Lesinski, Gregory B / Carson, William E. ·Department of Surgery, Division of Surgical Oncology, The Ohio State University, Arthur G James Cancer Hospital and Richard J SoloveResearch Institute, Columbus, Ohio 43210, USA. ·Mol Cancer Ther · Pubmed #20103601.

ABSTRACT: Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10-1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis.

16 Article Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines. 2009

Bill, Matthew A / Bakan, Courtney / Benson, Don M / Fuchs, James / Young, Gregory / Lesinski, Gregory B. ·Department of Internal Medicine, Division of Hematology and Oncology, 302B Comprehensive Cancer Center, Columbus, OH 43210, USA. ·Mol Cancer Ther · Pubmed #19723881.

ABSTRACT: Curcumin has potential as a chemopreventative and chemotherapeutic agent, but its interactions with clinically relevant cytokines are poorly characterized. Because cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses >10 micromol/L. Immunoblot analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, poly ADP ribose polymerase cleavage, reduced Bcl-2, and decreased basal phosphorylated signal transducers and activators of transcription 3 (STAT3). Despite its proapoptotic effects, curcumin pretreatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and downstream gene transcription following IFN-alpha and IFN-gamma as determined by immunoblot analysis and real time PCR, respectively. Pretreatment of peripheral blood mononuclear cells from healthy donors with curcumin also inhibited the ability of IFN-alpha, IFN-gamma, and interleukin-2 to phosphorylate STAT proteins critical for their antitumor activity (STAT1 and STAT5, respectively) and their respective downstream gene expression as measured by real time PCR. Finally, stimulation of natural killer (NK) cells with curcumin reduced the level of interleukin-12-induced IFN-gamma secretion, and production of granzyme b or IFN-gamma upon coculture with A375 melanoma cells or NK-sensitive K562 cells as targets. These data show that although curcumin can induce apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant cytokines that possess antitumor properties.

17 Article Bortezomib pre-treatment prolongs interferon-alpha-induced STAT1 phosphorylation in melanoma cells. 2009

Lesinski, Gregory B / Benninger, Kristen / Kreiner, Melanie / Quimper, Megan / Young, Gregory / Carson, William E. ·Division of Hematology and Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital, Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. gregory.lesinski@osumc.edu ·Cancer Immunol Immunother · Pubmed #19396596.

ABSTRACT: Bortezomib is a proteasome inhibitor that can synergize with interferon-alpha (IFN-alpha) to induce apoptosis in melanoma cells in vitro and inhibit tumor growth in vivo. We hypothesized that proteasome inhibition may be an effective means to sensitize melanoma cells to the direct effects of IFN-alpha. Pre-treatment of human melanoma cells with bortezomib led to significantly increased transcription of interferon-stimulated genes as determined by real-time PCR. Flow cytometric and immunoblot analyses indicated that the enhanced direct actions of IFN-alpha on melanoma cells were the result of prolonged phosphorylation of STAT1 (P-STAT1) on both the Tyrosine(701) and Serine(727) residues. In contrast, the enhanced IFN-alpha-induced P-STAT1 was not observed in peripheral blood mononuclear cells that were pre-treated with bortezomib. These data suggest that proteasome inhibition represents a mechanism to enhance the direct effects of IFN-alpha on melanoma cells thereby complementing its immunostimulatory properties.