The HIV Protease Inhibitor Nelfinavir Down-Regulates RET Signaling and Induces Apoptosis in Medullary Thyroid Cancer Cells

Kushchayeva, Yevgeniya; Jensen, Kirk; Recupero, Antony; Costello, John; Patel, Aneeta; Kłubo-Gwieździńska, Joanna; Boyle, Lisa; Burman, Kenneth D.; Vasko, Vasyl

doi:10.1210/jc.2013-3369

Cited by 32 publications

(35 citation statements)

References 41 publications

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“…We have reported previously that NFV inhibited the viability of medullary thyroid cancer cells, decreased the level of RET protein and blocked the activation of RET downstream targets (phosphorylated ERK, phosphorylated AKT and p70S6K/pS6) (Kushchayeva et al 2014b). These findings suggested that NFV could be effective against differentiated thyroid cancer cells with mutations in the PI3K/AKT pathway, as well as in tumors with activating mutations in MAPK-BRAF-ERK signaling.…”

Section: Introductionmentioning

confidence: 65%

Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells

Jensen¹,

Bikas²,

Patel³

et al. 2017

Endocrine-Related Cancer

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The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1-20 µM) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determined using real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial-mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 µM) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of γH2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 µM) resulted in caspase-3 cleavage in all examined cells. NFV (20 µM) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Our data suggest that NFV has a potential to become a new thyroid cancer therapeutic agent.

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Section: Introductionmentioning

confidence: 65%

Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells

Jensen¹,

Bikas²,

Patel³

et al. 2017

Endocrine-Related Cancer

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“…MTC can present as a hereditary disease in 25% of cases as a phenotype of multiple endocrine neoplasia type II (MEN2) syndromes A and B, or as a sporadic disease in 75% of cases (10). Constitutively activating mutations in RET cause almost all hereditary occurrences and approximately 50% of sporadic cases (11); thus, this protein has been the primary focus of drug development.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional targeting of oncogene addiction in medullary thyroid cancer

Valenciaga

Saji

Yu³

et al. 2018

JCI Insight

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Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

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“…The HIV-protease inhibitor nelfinavir has been shown to decrease RET expression and induce apoptosis in medullary thyroid cancer cells, but clinical studies are needed to prove its efficacy in treating MTC [62].…”

Section: Experimental Therapiesmentioning

confidence: 99%

A Perspective on the Current Medical Approach of Advanced Medullary Thyroid Carcinoma

Valea¹,

Georgescu²

2016

Thyroid Cancer - Advances in Diagnosis and Therapy

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Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor (NET), which originates in neural crest-derived calcitonin-producing C-cells. It occurs either sporadically or as a result of a germline mutation in the RET proto-oncogene, as in multiple endocrine neoplasia (MEN) syndrome type 2A including its variant familial MTC (FMTC) and type 2B. Currently, the only curative treatment for MTC is surgery, accompanied by lymph node dissection. However, the outcome is largely dependent on disease staging, with lymph node and distant metastases often identified at diagnosis, particularly in sporadic forms. Furthermore, the presence of cervical lymph node invasion at surgery predicts residual disease. The development of new treatments is strongly motivated by: (a) the low surgical cure rate when cervical lymph node metastases are present at the time of initial surgery, with 90% of patients having residual disease, (b) the high prevalence of distant metastases at initial diagnosis (lungs, bones and liver) and (c) the poor outcome in patients receiving cytotoxic chemotherapeutic agents. Herein, we focus on current nonsurgical options and perspectives in the treatment of MTC with emphasis on last year's FDA-approved tyrosine kinase inhibitors (TKIs) and other systemic therapies that need to be considered in the setting of advanced disease.

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The HIV Protease Inhibitor Nelfinavir Down-Regulates RET Signaling and Induces Apoptosis in Medullary Thyroid Cancer Cells

Abstract: NFV has a wide spectrum of activity against MTC cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of NFV molecular targets in metastatic MTC suggests that NFV has a potential to become a thyroid cancer therapeutic agent.

Cited by 32 publications

References 41 publications

Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells

Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells

Transcriptional targeting of oncogene addiction in medullary thyroid cancer

A Perspective on the Current Medical Approach of Advanced Medullary Thyroid Carcinoma

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