Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance....

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Bibliographic Details
Published in:Cancers Vol. 13; no. 9; p. 2045
Main Authors: Loehr, Amanda R, Pierpont, Timothy M, Gelsleichter, Eric, Galang, Anabella Maria D, Fernandez, Irma R, Moore, Elizabeth S, Guo, Matthew Z, Miller, Andrew D, Weiss, Robert S
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 23-04-2021
MDPI
Subjects:
Amino acids
Antipsychotics
Cancer therapies
Cell differentiation
Chemoresistance
Chemotherapy
Fibroblasts
Genotoxicity
Immunosuppressive agents
Laboratory animals
Malignancy
Metastasis
Neoplasia
Pluripotency
Psychotropic drugs
Salinomycin
Stem cell transplantation
Stem cells
Testes
Testicular cancer
Thioridazine
Tumors
Xenografts
United States > US
testicular germ cell tumor
cancer stem cells
embryonal carcinoma
pluripotency
differentiation therapy
nonseminoma
thioridazine
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Summary:Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.
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ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13092045