Sensitization to gimatecan-induced apoptosis by tumor necrosis factor-related apoptosis inducing ligand in prostate carcinoma cells

Paola Perego, Emilio Ciusani, Laura Gatti, Nives Carenini, Elisabetta Corna, Franco Zunino

Research output: Contribution to journalArticle

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Abstract

Since the intrinsic resistance of prostate carcinoma likely reflects a low susceptibility to drug-induced apoptosis, in this study we explored the possibility of sensitizing prostate carcinoma cells to apoptosis by combination of TRAIL with camptothecins. Indeed, these agents are known to activate different pathways of apoptosis. Topotecan- and gimatecan induced moderate up-regulation of TRAIL-R1 and -R2 which resulted in a different cell response to the combination in androgen-independent cells (DU-145 and PC-3). In DU-145 cells apoptosis was increased by lower TRAIL concentrations and was earlier than in PC-3 cells, as shown using Annexin V-binding assay. The relative resistance of PC-3 cells to drug-induced apoptosis was associated with constitutive Akt activation, higher levels of cFLIP-L and Bcl-2, and lower levels of Bax. The different expression/activation of apoptosis-related factors appears to influence the sensitization of prostate carcinoma cells by TRAIL. Potentiation of camptothecin-induced apoptosis by TRAIL appears dependent on cooperation between extrinsic and intrinsic pathways, as documented by loss of the sensitization to apoptosis following reduction of caspase 8 after small interfering RNA transfection. The efficacy of the approach may be critically dependent on the intrinsic susceptibility to apoptosis of different tumors. These observations support that the activation of multiple signals could enhance apoptotic response and suggest the therapeutic interest of the TRAIL/camptothecin combination.

Original languageEnglish
Pages (from-to)791-798
Number of pages8
JournalBiochemical Pharmacology
Volume71
Issue number6
DOIs
Publication statusPublished - Mar 14 2006

Fingerprint

Prostate
Tumor Necrosis Factor-alpha
Cells
Apoptosis
Ligands
Carcinoma
Camptothecin
Chemical activation
Topotecan
ST 1481
Caspase 8
Annexin A5
Pharmaceutical Preparations
Small Interfering RNA
Androgens
Transfection
Tumors
Assays
Up-Regulation
Neoplasms

Keywords

  • Apoptosis
  • Camptothecins
  • Cell sensitivity
  • Gimatecan
  • Prostate carcinoma
  • TRAIL

ASJC Scopus subject areas

  • Pharmacology

Cite this

Sensitization to gimatecan-induced apoptosis by tumor necrosis factor-related apoptosis inducing ligand in prostate carcinoma cells. / Perego, Paola; Ciusani, Emilio; Gatti, Laura; Carenini, Nives; Corna, Elisabetta; Zunino, Franco.

In: Biochemical Pharmacology, Vol. 71, No. 6, 14.03.2006, p. 791-798.

Research output: Contribution to journalArticle

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