title: 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.
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 IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/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 G(0)-G(1) and G(2)-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.
authors.affiliation: Institute of Cancer Research, National Health Research Institutes, 7th Floor, No. 161, Section 6, Min-Chuan East Road, Taipei 114, Taiwan, Republic of China.
authors.forename: Shin-Hun
authors.initials: SH
authors.lastname: Juang
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lung
authors.forename: Pi-Chen
authors.initials: PC
authors.lastname: Hsu
authors.forename: Kuo-Shun
authors.initials: KS
authors.lastname: Hsu
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Li
authors.forename: Pao-Chiung
authors.initials: PC
authors.lastname: Hong
authors.forename: Her-Shyong
authors.initials: HS
authors.lastname: Shiah
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Wang
authors.forename: Leeyuan
authors.initials: L
authors.lastname: Huang
authors.forename: Tom S
authors.initials: TS
authors.lastname: Chen
authors.forename: Shyh-Fong
authors.initials: SF
authors.lastname: Chen
authors.forename: Kuo-Chu
authors.initials: KC
authors.lastname: Fu
authors.forename: Cheng-Li
authors.initials: CL
authors.lastname: Hsu
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Lin
authors.forename: Ching-Jer
authors.initials: CJ
authors.lastname: Chang
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Ashendel
authors.forename: Thomas C K
authors.initials: TC
authors.lastname: Chan
authors.forename: Kai-Ming
authors.initials: KM
authors.lastname: Chou
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002292:Carcinoma, Renal Cell / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D019073:HT29 Cells; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C517977:2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D006575:Heterocyclic Compounds, 3-Ring; D016566:Organoselenium Compounds; D011758:Pyrroles; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha