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Zewdu A, Lopez G, Braggio D, et al. Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis. Clin Exp Pharmacol. 2016;6(6)doi: 10.4172/2161-1459.1000221.
Zewdu, A., Lopez, G., Braggio, D., Kenny, C., Constantino, D., Bid, H. K., Batte, K., Iwenofu, O. H., Oberlies, N. H., Pearce, C. J., Strohecker, A. M., Lev, D., & Pollock, R. E. (2016). Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis. Clinical & experimental pharmacology, 6(6), . https://doi.org/10.4172/2161-1459.1000221
Zewdu, A, et al. "Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis." Clinical & experimental pharmacology vol. 6,6 (2016). doi: https://doi.org/10.4172/2161-1459.1000221
Zewdu A, Lopez G, Braggio D, Kenny C, Constantino D, Bid HK, Batte K, Iwenofu OH, Oberlies NH, Pearce CJ, Strohecker AM, Lev D, Pollock RE. Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis. Clin Exp Pharmacol. 2016 Nov;6(6). doi: 10.4172/2161-1459.1000221. Epub 2016 Oct 24. PMID: 28184331; PMCID: PMC5295762.
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Clin Exp Pharmacol. 2016 Nov;6(6). doi: 10.4172/2161-1459.1000221. Epub 2016 Oct 24.

Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis.

Clinical & experimental pharmacology

A Zewdu, G Lopez, D Braggio, C Kenny, D Constantino, H K Bid, K Batte, O H Iwenofu, N H Oberlies, C J Pearce, A M Strohecker, D Lev, R E Pollock

Affiliations

  1. Department of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
  2. Department of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Resonant Therapeutics, Inc., Ann Arbor, Michigan, USA.
  3. Department of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Pathology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  4. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
  5. Mycosynthetix, Inc., Hillsborough, North Carolina, USA.
  6. Department of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio, USA.
  7. Surgery B, Sheba Medical Center, Tel Aviv, Israel.

PMID: 28184331 PMCID: PMC5295762 DOI: 10.4172/2161-1459.1000221

Abstract

OBJECTIVE: The heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetically complex STS, development of therapies demonstrating potency against this STS cluster is especially challenging and yet greatly needed. Verticillin A is a small molecule natural product with demonstrated anticancer activity; however, the efficacy of this agent has never been evaluated in STS. Therefore, the goal of this study was to explore verticillin A as a potential STS therapeutic.

METHODS: We performed survival (MTS) and clonogenic analyses to measure the impact of this agent on the viability and colony formation capability of karyotypically complex STS cell lines: malignant peripheral nerve sheath tumor (MPNST) and leiomyosarcoma (LMS). The in vitro effects of verticillin A on apoptosis were investigated through annexin V/PI flow cytometry analysis and by measuring fluorescently-labeled cleaved caspase 3/7 activity. The impact on cell cycle progression was assessed via cytometric measurement of propidium iodide intercalation.

RESULTS: Treatment with verticillin A resulted in decreased STS growth and an increase in apoptotic levels after 24 h. 100 nM verticillin A induced significant cellular growth abrogation after 24 h (96.7, 88.7, 72.7, 57, and 39.7% reduction in LMS1, S462, ST88, SKLMS1, and MPNST724, respectively). We observed no arrest in cell cycle, elevated annexin, and a nearly two-fold increase in cleaved caspase 3/7 activity in all MPNST and LMS cell lines. Control normal human Schwann (HSC) and aortic smooth muscle (HASMC) cells displayed higher tolerance to verticillin A treatment compared to sarcoma cell lines, although toxicity was seen in HSC at the highest treatment dose.

CONCLUSION: Advancement in the treatment of karyotypically complex STS is confounded by the high level of genetic abnormalities found in these diseases. Consequently, the identification and investigation of novel therapies is greatly needed. Our data suggest that verticillin A selectively inhibits MPNST and LMS growth via induction of apoptosis while exhibiting minimal to moderate effects on normal cells, pointing to verticillin A as a potential treatment for MPNST and LMS, after additional preclinical validation.

Keywords: Apoptosis; Epipolythiodioxopiperazine alkaloid; LMS; Leiomyosarcoma; MPNST; Malignant peripheral nerve sheath tumor; STS; Soft tissue sarcoma; Verticillin A

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