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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

NC381, a Novel Anticancer Agent, Arrests the Cell Cycle in G0-G1 and Inhibits Lung Tumor Cell Growth in Vitro and in Vivo

Ming-Yu Cao, Yoon Lee, Ning-Ping Feng, Raed A. Al-Qawasmeh, Stéphane Viau, Xiao-Ping Gu, Leo Lau, Hongnan Jin, Ming Wang, Aikaterini Vassilakos, Jim A. Wright and Aiping H. Young
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 538-546; DOI: https://doi.org/10.1124/jpet.103.059618
Ming-Yu Cao
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Yoon Lee
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Ning-Ping Feng
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Raed A. Al-Qawasmeh
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Stéphane Viau
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Xiao-Ping Gu
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Leo Lau
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Hongnan Jin
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Ming Wang
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Aikaterini Vassilakos
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Jim A. Wright
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Aiping H. Young
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Abstract

Although clotrimazole (CLT), an antifungal drug, inhibits tumor cell proliferation and angiogenesis, its clinical application is hampered by significant hepatotoxicity due to the presence of an imidazole moiety. In our attempts to develop CLT analogs that are devoid of imidazole and are as efficacious as CLT, one pharmacophore designated NC381 was generated and shown to inhibit tumor cell growth via a mechanism similar to that of CLT. In vitro, treatment of NCI-H460 nonsmall cell lung cancer (NSCLC) cells with NC381 inhibited growth in a time-dependent manner. Flow cytometric analysis demonstrated that the decrease in cell growth was associated with inhibition of cell cycle progression at the G1-S phase transition, resulting in G0-G1 arrest. There was a concomitant inhibition of cyclin D1 expression and subsequent reduction in the formation of the cyclin D1-CDK4 complex. Consistent with a decrease in the cyclin D1-CDK4 complex, NC381 treatment resulted in significant inhibition of pRb phosphorylation. There also were changes in the activity of cell cycle-related proteins, including p16Ink4 and p27Kip1. Together, these results are consistent with a model in which NC381 arrests cell cycle progression via inhibition of the pathway that promotes exit from the G1 phase of the cell cycle. Furthermore, the clinical applicability of NC381 was evaluated in an in vivo murine xenograft model of human NSCLC (NCI-H460). NC381 treatment resulted in significant inhibition of tumor growth. Given the poor prognosis and the limited treatment options available, the present results underscore the potential of NC381 in the treatment of human NSCLC.

Footnotes

  • Financial support for the research has been provided by Lorus Therapeutic Inc.

  • DOI: 10.1124/jpet.103.059618.

  • ABBREVIATIONS: NSCLC, nonsmall cell lung cancer; CDK, cyclin dependent kinase; CLT, clotrimazole; FBS, fetal bovine serum; pRb, product of the retinoblastoma susceptibility gene; GI50, 50% of growth inhibition; Ink4, inhibitor of CDK4; Kip1, kinase inhibitory protein 1; Cip, CDK interacting protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline.

    • Received September 5, 2003.
    • Accepted October 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

NC381, a Novel Anticancer Agent, Arrests the Cell Cycle in G0-G1 and Inhibits Lung Tumor Cell Growth in Vitro and in Vivo

Ming-Yu Cao, Yoon Lee, Ning-Ping Feng, Raed A. Al-Qawasmeh, Stéphane Viau, Xiao-Ping Gu, Leo Lau, Hongnan Jin, Ming Wang, Aikaterini Vassilakos, Jim A. Wright and Aiping H. Young
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 538-546; DOI: https://doi.org/10.1124/jpet.103.059618

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

NC381, a Novel Anticancer Agent, Arrests the Cell Cycle in G0-G1 and Inhibits Lung Tumor Cell Growth in Vitro and in Vivo

Ming-Yu Cao, Yoon Lee, Ning-Ping Feng, Raed A. Al-Qawasmeh, Stéphane Viau, Xiao-Ping Gu, Leo Lau, Hongnan Jin, Ming Wang, Aikaterini Vassilakos, Jim A. Wright and Aiping H. Young
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 538-546; DOI: https://doi.org/10.1124/jpet.103.059618
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