Chemotherapeutic Drugs Induce PPAR-γ Expression and Show Sequence-Specific Synergy with PPAR-γ Ligands in Inhibition of Non-Small Cell Lung Cancer1

Preclinical studies have shown that peroxisome proliferator-activated receptor γ (PPAR-γ) ligands can exert antitumor effects against non-small cell lung cancer (NSCLC) and a variety of other cancers. In this study, we investigate the potential use of a PPAR-γ ligand, troglitazone (Tro), in combination with either of two chemotherapeutic agents, cisplatin (Cis) or paclitaxel (Pac), for the treatment of NSCLC. In vitro, treatment of NSCLC cell lines with Tro potentiated Cis- or Pac-induced growth inhibition. The potentiation of growth inhibition was observed only when Cis or Pac treatment was followed by Tro and not vice versa, demonstrating a sequence-specific effect. Median effect analysis revealed a synergistic interaction between Tro and Cis in the inhibition of NSCLC cell growth and confirmed the sequence-specific effect. We also found that Cis or Pac up-regulated the expression of PPAR-γ protein, accounting for the observed sequence-specific synergy. Similarly, experiments performed using a NSCLC xenograft model demonstrated enhanced effectiveness of combined treatment with Cis and PPAR-γ ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-γ expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-γ ligands and chemotherapeutic agents for lung cancer treatment

Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer

Purpose These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vitro and, if so, how. Experimental Design Ritonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)-positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft. Results ER-positive estradiol-dependent lines (IC50, 12–24 µmol/L) and ER-negative (IC50, 45 µmol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-α levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 ± 8 µmol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (KD, 7.8 µmol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90α short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations. Conclusions Ritonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference