NC381, a novel anticancer agent, arrests the cell cycle in G0-G1 and inhibits lung tumor cell growth in vitro and in vivo.
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 G(1)-S phase transition, resulting in G(0)-G(1) 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 p16(Ink4) and p27(Kip1). 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 G(1) 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.
Cao
Ming-Yu
MY
Lorus Therapeutics Inc., Toronto, ON, Canada, M9W 4Z7. mcao@lorusthera.com
Lee
Yoon
Y
Feng
Ning-Ping
NP
Al-Qawasmeh
Raed A
RA
Viau
Stéphane
S
Gu
Xiao-Ping
XP
Lau
Leo
L
Jin
Hongnan
H
Wang
Ming
M
Vassilakos
Aikaterini
A
Wright
Jim A
JA
Young
Aiping H
AH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003022:Clotrimazole / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482406:NC381 agent; D016160:Retinoblastoma Protein; D003022:Clotrimazole