Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models.

Nicole Pinto,Jalna Meens,Laurie Ailles,Myung W Han,John W Barrett,Danielle Macneil,Joe S Mymryk,Neil Mundi,Paul C Boutros,Anthony C Nichols,Krupal Patel,Farhad Ghasemi,Alessandro Datti,Kara M Ruicci,John Yoo,Stephenie D Prokopec,Kevin Fung,Imran M Khan,Irina V Lebedeva

doi:10.1371/journal.pone.0239315

Abstract

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.

Highlights

Anaplastic thyroid cancer (ATC) is a rare form of undifferentiated thyroid cancer which progresses rapidly and is almost universally fatal [1,2,3]
The use of smallmolecule kinase inhibitors to target key proteins has become an attractive strategy across many cancer types including a number of prospective targeted therapies which have been identified for inhibition of various putative targets in ATC including sorafenib (VEGFR), axitinib (VEGFR), vemurafenib and dabrafenib (BRAF/MEK), imatinib (PDGFR), and selumetinib (MEK 1 and 2) [9]
As flavopiridol has been reported to be cytostatic [21], we assessed the clonogenic capabilities of CAL62 and BHT-101 cells when treated with 60 nM and 125 nM concentrations of flavopiridol

Summary

Introduction

Anaplastic thyroid cancer (ATC) is a rare form of undifferentiated thyroid cancer which progresses rapidly and is almost universally fatal [1,2,3]. Even with the use of conventional therapies such as surgical resection, chemotherapy and radiation, improvements in overall patient survival for those diagnosed with ATC have not changed in the past decade, remaining at a dismal mortality rate of close to 100% [1,8]. The failure to increase survival rates of those suffering from ATC using the aforementioned treatment strategies has shifted current efforts to determine which molecular targets are “actionable” and can be used to halt the otherwise rapid disease progression. The use of smallmolecule kinase inhibitors to target key proteins has become an attractive strategy across many cancer types including a number of prospective targeted therapies which have been identified for inhibition of various putative targets in ATC including sorafenib (VEGFR), axitinib (VEGFR), vemurafenib and dabrafenib (BRAF/MEK), imatinib (PDGFR), and selumetinib (MEK 1 and 2) [9]. Cell cycle inhibitors, cyclin-dependent kinase (CDK) inhibitors, are under active investigation in a number of other cancer types, including breast cancer and non-small cell lung cancer [10,11,12]

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Discussion

Conclusion