A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo
Open accessAbstract
Background Most medullary thyroid carcinomas (MTC) recur or progress despite curative resection. Current targeted therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build on previous in vitro work and evaluate withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.Methods A total of 5 million DRO-81-1 human MTC cells injected in the left posterior neck of nu/nu mice generated metastases uniformly to the liver, spleen, and/or lungs. Treatment with WA (8 mg/kg/day, intraperitoneally, for 21 days) was started for neoplasms > 100 mm(3). Endpoints were survival, neoplasm > 15,00 mm(3), decreased body weight, or body score (all measured three times/wk).Results All controls (saline; n = 5) died or deteriorated from metastatic disease by 7 weeks postinjection. All treated animals were alive (WA; n = 5), having tumor regression and growth delay without toxicity or weight loss at 6 weeks posttreatment (P < .01). Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western blot analysis in a dose-dependent manner (almost complete inhibition with treatment of 5 μM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels.Conclusion WA is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation.
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From Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects (2021) · cites this paper as [299]
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Self-citation
- Authors
- Samadi, A. K., Mukerji, R., Shah, A., Timmermann, B. N., & Cohen, M. S.
- Affiliations
- University of Kansas Medical Center (US)
- University of Kansas (US)
- ORCID
- Cohen, Mark S.
- Venue
- Surgery
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 148
- Issue
- 6
- Pages
- 1228-1236
- ISSN
- 0039-6060 (ISSN-L)
- PMC
- PMC3088305
- OpenAlex
- W2006319307
- Cited by
- 60
- References
- 24
- Citations by year
- 2024: 4 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Surgery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- KU ScholarWorks (University of Kansas) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (5p20rr015563-08)
- National Cancer Institute (L30 CA136330)
- National Center for Research Resources (P20-RR015563)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- withaferin A, RET inhibitors, medullary thyroid carcinoma, metastatic thyroid cancer, natural products, tumor regression, targeted therapy
- MeSH terms
- Animals, Antineoplastic Agents, Calcitonin, Humans, Mice, Nude, Neural Crest, Thyroid Neoplasms, Transplantation, Heterologous, Carcinoma, Neuroendocrine, Biopsy, Fine-Needle, Proto-Oncogene Proteins c-ret, Mice, Withanolides
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