Effects of the Mammalian Target of Rapamycin Inhibitor CCI-779 Used Alone or with Chemotherapy on Human Prostate Cancer Cells and Xenografts

Abstract

Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/ /PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/ /or Western blotting. Expression of phospho-Akt/ /PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779. (Cancer Res 2005; 65(7): 2825-31)

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…At this point there are few preclinical studies in CaP evaluating mTOR inhibitors in combination with other therapeutics. The mTOR inhibitors rapamycin and CCI-779 in combination with doxorubicin, mitoxantrone, docetaxel, and receptor tyrosine kinase inhibitors have yielded mixed results in studies with CaP cell lines and/or xenografts [9,13,40]. In our studies, we failed to detect synergistic effects with combination therapies, but a trend toward more pronounced inhibition was observed as more agents were added.…”

“…Consistent with this, PTEN-negative tumors are particularly good targets for mTOR inhibitors [9,10]. mTOR, originally identified as the mammalian target of rapamycin, is a serine/threonine kinase that plays a central role in control of translation and also regulates anti-apoptotic signals (reviewed in Castedo et al [11]).…”

PTEN Deficiency Is Fully Penetrant for Prostate Adenocarcinoma in C57BL/6 Mice via mTOR-Dependent Growth

“…30 Previous studies in human prostate cancer cells and xenografts in immunocompromised mice demonstrated that the rapamycin analog CCI-779 was effective at suppressing mTOR signaling as evidenced by decreased phospho-S6 levels determined by immunostaining and Western analysis. 45 Further, a reduction in proliferation was observed in xenografts of mice bearing PTEN-negative PC3 cells on treatment with CCI-779, linking mTOR activation on loss of PTEN function to cell growth. 46 Together with our data, these studies demonstrate that Pten-deficient preclinical models have utility for evaluating mTOR as a therapeutic target for prostate cancer.…”

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

“…Chemical inhibitors targeting the catalytic unit of PI3K, such as LY294002 and Wortmanin, induce a potent apoptotic response in most PrCa cell lines including LNCaP, LAPC4 and LAPC9 (Lin et al, 1999). Rapamycin or CCI-779 targeting of mTOR, a main PI3K/Akt growth effector, can promote cell cycle arrest of PrCa cell lines, xenografts (Wu et al, 2005) and reversion of prostatic intraepithelial neoplasia (PIN) phenotype (Majumder et al, 2004); small molecule inhibition of Akt 1 and 2 isoforms have also proven effective inducers of caspase-3 (DeFeo-Jones et al, 2005). However, inhibitors targeting MAPK (e.g.…”