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We examined the effect of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, and N-(9-fluorenyl-methyloxycarbonyl)-L-leucine (F-L-Leu), a peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist, separately and combined, on the development of methylnitrosourea (MNU)-induced rat mammary gland carcinogenesis. Celecoxib and F-L-Leu significantly reduced tumor incidence and multiplicity (P < 0.05). Combining both agents exerted higher (synergistic) cancer inhibition than separate treatments (P < 0.05). The effects of the test drugs on COX-2 and PPAR␥ expression and on the synthesis of prostaglandin E 2 (PGE 2 ) and 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) were examined in rat mammary normal (MNUuntreated), uninvolved, and tumor (MNU-treated) tissues. Celecoxib and F-L-Leu, separately, inhibited COX-2 and up-regulated PPAR␥ expression. These effects were paralleled by inhibition of PGE 2 synthesis and up-regulation of 15d-PGJ 2 . Combined treatment resulted in higher alterations in COX-2 and PPAR␥ transcripts and PG synthesis compared with separate administrations. The effect of the test agents on Bcl 2 , BAX, and protein kinase C␣ expression levels were examined in the rat mammary gland and the pro-(BAX:Bcl 2 ) and anti-[PKC␣*(Bcl 2 /BAX)] apoptotic ratios were evaluated. Each drug increased the proapoptotic ratio by 2-to 7-fold and reduced the antiapoptotic ratio by 2-to >8-fold in all tissues. Combined treatment, however, resulted in >9-to 14-fold up-regulation in the proapoptotic processes and 15-to >30-fold down-regulation in the antiapoptotic ones. Analyses were also carried out on the drug-induced modulation of cell cycle regulators and proliferation markers (cyclindependent kinase 1 and proliferating cell nuclear antigen). F-L-Leu and celecoxib each reduced the cyclin-dependent kinase 1 and proliferating cell nuclear antigen expression in the tumor. Higher down-regulation was attained in all tissues by combined treatment where cyclin-dependent kinase 1 and proliferating cell nuclear antigen almost retained the expression levels observed in the normal glands. In conclusion, simultaneous targeting of COX-2 and PPAR␥ may inhibit mammary cancer development more effectively than targeting each molecule alone. COX-2 inhibitors and PPAR␥ agonists coordinately mediate their anticancer effect via both COX-dependent (inhibition of COX-2, activation of PPAR␥, and modulation PG synthesis) and COX-independent (induction of proapoptotic factors and inhibition of cell proliferation) pathways.

HIV-1 Tat is a potent transcriptional activator of the viral promoter with the ability to modulate a number of cellular regulatory circuits including apoptosis. Tat exerts its effects through interaction with viral as well as cellular proteins. Here, we studied the influence of p73, a protein that is implicated in apoptosis and cell cycle control, on Tat apoptotic function in the central nervous system. We recently demonstrated the ability of Tat to associate with p73, and that this association modulates Tat transcriptional activity (Amini et al., Mol Cell Biol 2005; 18: 8126-8138). We demonstrated that p73 interferes with Tat-mediated apoptosis by preventing the up-regulation of Bax and down-regulation of Bcl-2 proteins in astrocytes. Thus, the interplay between Tat and p73 may affect Tat contribution to apoptotic events in the brain, limiting its involvement in the neuropathology often observed in the brains of HIV-1 patients.

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