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

Shin Hun Juang, Chia Chi Lung, Pi Chen Hsu, Kuo Shun Hsu, Yu Chen Li, Pao Chiung Hong, Her Shyong Shiah, Ching Chuan Kuo, Ching Wei Huang, Yu Chin Wang, Leeyuan Huang, Tom S. Chen, Shyh Fong Chen, Kuo Chu Fu, Cheng Li Hsu, Meng Ju Lin, Ching Jer Chang, Curtis L. Ashendel, Thomas C.K. Chan, Kai Ming ChouJang Chang Chang

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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 topolsomerase-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 p2lWAF1 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.

Original languageEnglish
Pages (from-to)193-202
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 1 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Juang, S. H., Lung, C. C., Hsu, P. C., Hsu, K. S., Li, Y. C., Hong, P. C., Shiah, H. S., Kuo, C. C., Huang, C. W., Wang, Y. C., Huang, L., Chen, T. S., Chen, S. F., Fu, K. C., Hsu, C. L., Lin, M. J., Chang, C. J., Ashendel, C. L., Chan, T. C. K., ... Chang, J. C. (2007). 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. Molecular Cancer Therapeutics, 6(1), 193-202. https://doi.org/10.1158/1535-7163.MCT-06-0482