Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer

Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 300 Brookline Avenue, Boston, MA 02215, USA.
Cancer biology & therapy (Impact Factor: 3.07). 03/2007; 6(2):195-201. DOI: 10.4161/cbt.6.2.3588
Source: PubMed

ABSTRACT Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway is a potentially useful therapeutic strategy in the treatment of advanced prostate cancer. However mTOR antagonists used as single agents are not likely to result in dramatic clinical responses, so that it is useful to identify prospective agents that might be useful in combination. We treated CWR22Rv1 and LNCaP prostate cancer cells with an mTOR inhibitor, rapamycin, alone, or in combination with either of two receptor protein kinase (RTK) inhibitors. We assessed the effects of these treatments on cell survival and activation of down-stream mTOR target proteins. Treatment with either PD16839, an EGFr antagonist, or imatinib mesylate (Gleevec), a PDGFr, c-kit and bcr/abl antagonist, enhanced the anti-proliferative effects of rapamycin. We therefore assessed the effects of treatment with the RTK antagonist alone and in combination with rapamycin on mTOR targeted proteins. RTK antagonists alone had no effect or paradoxically increased phosphorylation of the mTOR targeted proteins, p70 S6 kinase and ribosomal S6. In contrast, when these cells were treated with either RTK antagonist in the presence of rapamycin, there was a dramatic decrease in phosphorylation of these two mTOR-targeted proteins. These effects were not mediated through phospho-AKT. Since two separate RTK antagonists had additive antiproliferative effects in combination with an mTOR antagonist and were associated with a dramatic decrease in mTOR targeted proteins in cells with or without PTEN expression, the strategy deserves further evaluation for the treatment of prostate cancer.

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    • "An additional study revealed the synergistic effects of RPM and chemotherapeutic agents against tumor cells; RPM was reported to increase the cytotoxicity of cisplatin by sensitizing human promyelocytic leukemia and ovarian cancer cells to the drug, thereby inducing apoptosis (15). However, receptor tyrosine kinase inhibitors only demonstrate additive effects in combination with RPM in the treatment of prostate cancer (16). A previous study indicated that IFN-α suppresses the phosphoinositide 3 kinase and mTOR signaling pathways (17). "
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    ABSTRACT: The aim of the present study was to investigate the antiproliferative effects of interferon (IFN)-α and rapamycin (RPM) on renal cell carcinoma (RCC) cells and examine the synergistic growth suppression conferred by IFN-α and RPM. The effects of IFN-α and/or RPM on RCC cells were determined using a WST-1 assay and the synergy of IFN-α and RPM against three RCC cell lines was analyzed with isobolographic analysis. The expression of mammalian target of rapamycin (mTOR) was downregulated by RNAi, and the expression and phosphorylation of proteins in the mTOR pathway following treatment with IFN-α and/or RPM was examined by western blot analysis. The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines. The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC. IFN-α and RPM alone decreased the phosphorylation of mTOR, p70 S6 kinase, S6 and 4E binding protein 1, and IFN-α significantly enhanced the RPM-induced suppression of the mTOR pathway. However, in RCC cells with low mTOR activity, the synergy of IFN-α and RPM was eliminated. Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells. Thus, mTOR may serve as an effective therapeutic target in the treatment of advanced RCC.
    Experimental and therapeutic medicine 07/2014; 8(1):267-273. DOI:10.3892/etm.2014.1691 · 1.27 Impact Factor
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    • "These inhibitors of mTOR bind to the FK506-binding protein, FKBP-12, which then binds and inhibits mTOR [49, 50]. Synergistic effects of rapamycin and EGFR TKIs have been observed in several in vitro systems, including glioblastoma multiforme [51–53], prostate cancer [54, 55], pancreatic cancer [54], squamous cell carcinoma [56], renal cell carcinoma [57, 58], leukemia [59], cervical carcinoma [60], and non-small cell lung cancer [54]. Several other studies extended the efficacy of these combinations to xenograft experiments [54, 60, 61]. "
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    ABSTRACT: AKT1, a serine/threonine-protein kinase also known as AKT kinase, is involved in the regulation of various signalling downstream pathways including metabolism, cell proliferation, survival, growth, and angiogenesis. The AKT kinases pathway stands among the most important components of cell proliferation mechanism. Several approaches have been implemented to design an efficient drug molecule to target AKT kinases, although the promising results have not been confirmed. In this paper we have documented the detailed molecular insight of AKT kinase protein and proposed a probable doxorubicin based approach in inhibiting miR-21 based cancer cell proliferation. Moreover, the inhibition of miR-21 activation by raising the FOXO3A concentration seems promising in reducing miR-21 mediated cancer activation in cell. Furthermore, the use of next generation sequencing and computational drug design approaches will greatly assist in designing a potent drug molecule against the associated cancer cases.
    The Scientific World Journal 11/2013; 2013(5):756134. DOI:10.1155/2013/756134 · 1.73 Impact Factor
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    • "It is considered that single-agent inhibition may induce tumor cells to activate alternative pathways (Chaturvedi et al., 2009; Zuo et al., 2010). Multiple strategies to inhibit PI3K/ AKT pathway have been proposed and are in ongoing clinical trials (Buck et al., 2006; Faivre et al., 2006; Masiello et al., 2007; Wang et al., 2007). Antagonism of cell surface receptor and nonreceptor kinases could potentially disrupt the PI3K pathway by eliminating the stimulus for PI3K activation. "
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    ABSTRACT: This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor (EGFR) or/and mammalian target of rapamycin( mTOR) inhibitors with two endometrial cancer lines HEC-1A and Ishikawa. Treatment was with the EGFR inhibitor RG14620, the mTOR inhibitor rapamycin, and the conventional cytotoxic drug paclitaxel, alone or in combination. The 50% inhibitory concentration (IC50) and cell viability were determined by the MTT assay. Multiple drug effect/ combination indexes (CI) analysis was applied to assess interactions between paclitaxel and the two inhibitors. Apoptosis and cell cycling were evaluated by flow cytometry analysis. Western blotting was performed to evaluate the related protein alteration in PI3K/AKT signaling pathway. RG14620, rapamycin and paclitaxel showed obvious dose-dependent growth inhibition with time. The IC50 of paclitaxel at 24 hours decreased significantly when pretreated with low doses of RG14620 and Rapamycin alone or in combination. Moreover, combination index (CI) of paclitaxel with each inhibitor was larger than 1, indicating a synergistic effect between pairs of drugs in these two cell lines. FACS analysis showed the cell apoptosis rate increased with a synergistic effect. On Western blotting, activation of PI3K/AKT pathway was detected in both two cell lines in the control case. When paclitaxel was used as a single-agent or in combinations, the protein expression of PI3K/AKT pathway totally abated, especially in HEC-1A cells, suggesting a role in chemoresistance. The combination of three drugs induced the greatest over-expression of caspase-3. Combining targeted inhibitors with cytotoxic chemotherapy appears to be a promising strategy for the effective treatment of endometrial cancer which merits further clinical investigation.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(11):2951-7. · 2.51 Impact Factor
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