Multiple effects of the IGF-1R inhibitor PQIP on prostate cancer cells.

LB-19

The insulin-like growth factor (IGF) system plays an important role in a variety of physiological processes. The role of the IGF system in cancer has also been recognized, and shown to affect cell transformation, proliferation, survival, motility and migration. IGF-1R has been identified in normal prostate, prostate cancer and metastatic tissue. In addition, IGF-1R modulates AR localization and transcriptional activity. Hence, inhibition of IGF-1R kinase activity may be of therapeutic value in the treatment of prostate cancer. The IGF-1R inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-Phenyl-Quinolin-7-yl)-Imidazo[1,5-a]Pyrazin-8-ylamine (PQIP, OSI Pharmaceuticals, Farmingdale, NY) inhibited prostate cancer cell growth with an IC₅₀ = 3.6 μM. This compound inhibited IGF-1 and IGF-2 induced IGF1R phosphorylation as well as the activation of downstream targets Akt and p70S6 kinase. In androgen dependent LNCaP prostate cancer cells, androgen deprivation inhibited cell growth by 75.1% (p=0.0027), whereas PQIP inhibited growth of the same cells by 86.6% (p=0.0021). The combination of PQIP and androgen deprivation caused a small but significant additional inhibition (88.6% inhibition from controls, p=0.002, 54.13% inhibition over androgen deprivation alone, p<0.0001 and 15.02% inhibition over PQIP alone, p=0.005). This suggested that PQIP may be of greater effect in conjunction with androgen deprivation. We also tested the ability of these cells to inhibit the growth of an androgen-independent subline of LNCaP cells, LNAI, which were derived by prolonged culture of LNCaP cells in androgen-reduced media. PQIP inhibited growth of LNAI cells by 90.88%, p=0.0023. The mTOR inhibitor rapamycin reduced growth rates of LNAI cells as a single agent by 51.68%, p=0.019. In combination with the mTOR inhibitor rapamycin, PQIP inhibited the growth of LNAI cells by an additional 63%, p=0.015. Simultaneous treatment with 1 nM rapamycin and 5 μM PQIP reduced cell numbers on day 8 by 31.76% below that on day 2, p=0.00034, indicating the onset of cell death. These studies indicate that PQIP, alone or in conjunction with rapamycin, may be effective in reducing prostate tumor cells. In addition, PQIP inhibited IGF1R phosphorylation induced by radiation. Since stimulation of IGF1R phosphorylation may be a major cause of the development of resistance to radiation therapy, our data suggests that this effect may be counteracted by PQIP. Thus, PQIP may have multiple uses in prostate cancer treatment.