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Research Articles: Therapeutics, Targets, and Development

D-501036, a novel selenophene-based triheterocycle derivative, exhibits potent in vitro and in vivo antitumoral activity which involves DNA damage and ataxia telangiectasia–mutated nuclear protein kinase activation

¹ School of Pharmacy, China Medical University and the Department of Medical Research, China Medical University Hospital, Taichung; ² Institute of Cancer Research, National Health Research Institutes; Departments of ³ Pharmacology and ⁴ Medicinal Chemistry, Development Center for Biotechnology; ⁵ Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; ⁶ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana; and ⁷ Cell Biology and Neuroscience Program, University of South Alabama, Mobile, Alabama

Requests for reprints: Jang-Yang Chang, Institute of Cancer Research, National Health Research Institutes, 7th Floor, No. 161, Section 6, Min-Chuan East Road, Taipei 114, Taiwan, Republic of China. Phone: 886-2-2792-9682; Fax: 886-2-2792-9654. E-mail: jychang{at}nhri.org.tw

Abstract

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC₅₀ value in the nanomolar range. The IC₅₀ values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 µmol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G₀-G₁ and G₂-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036–induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036–mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036–induced DNA damage activated ataxia telangiectasia–mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21^WAF1 in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036–induced cell death was associated with DNA damage–mediated induction of ataxia telangiectasia–mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers. [Mol Cancer Ther 2007;6(1):193–202]

Grant support: CA-095-PP-04 of National Health Research Institutes, Taipei and National Science Council (NSC-94-2752-B-400-001-PAE and NSC-95-2320-B-039-034-MY2), Taipei, Taiwan, ROC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S-H. Juang and C-C. Lung contributed equally to this work.

⁸ Hong et al., personal communication.

Received 8/10/06; revised 10/17/06; accepted 11/22/06.