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Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones.
- Source :
-
Endocrine-related cancer [Endocr Relat Cancer] 2006 Jun; Vol. 13 (2), pp. 401-13. - Publication Year :
- 2006
-
Abstract
- Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
Cyclin D1 metabolism
Humans
Neoplasms drug therapy
PPAR gamma agonists
Thiazolidinediones chemistry
Thiazolidinediones therapeutic use
Antineoplastic Agents pharmacology
PPAR gamma physiology
Proteasome Endopeptidase Complex drug effects
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Thiazolidinediones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1351-0088
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Endocrine-related cancer
- Publication Type :
- Academic Journal
- Accession number :
- 16728570
- Full Text :
- https://doi.org/10.1677/erc.1.01182