Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

Abstract

Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60–87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.

Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo

“…mTOR activation can promote angiogenesis, tumor invasion, metastasis and the cell cycle. It plays a very important role in the occurrence, development and treatment of liver cancer (43)(44)(45)(46). Signal transducers and activators of transcription3 (STAT3), activation leads to increased expression of downstream target genes, leading to increased cell proliferation, cell survival, angiogenesis and immune system evasion.…”

Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

“…Similarly, everolimus was also investigated with low-dose patupilone, with promising results45 reconfirming a synergistic effect between mTOR inhibitors and MBAs in HCC cells. More interestingly, accompanying mechanistic studies demonstrated that the marked antitumor activity of the combination was not affected by further suppression of the mTOR signaling pathway compared with everolimus alone, but may be due to possible induction of apoptosis in these HCC models mediated by the combination treatment 45. The combination was also found to induce a significant reduction in microvessel density in tumors when compared to those treated with vehicle control, indicating potential antiangiogenic activity 45…”

“…Indeed, recent in vivo and in vitro studies have shown that a combination of mTOR inhibitor temsirolimus and low-dose vinblastine had a marked antitumor effect 106. Similarly, everolimus was also investigated with low-dose patupilone, with promising results45 reconfirming a synergistic effect between mTOR inhibitors and MBAs in HCC cells. More interestingly, accompanying mechanistic studies demonstrated that the marked antitumor activity of the combination was not affected by further suppression of the mTOR signaling pathway compared with everolimus alone, but may be due to possible induction of apoptosis in these HCC models mediated by the combination treatment 45.…”

mTOR signaling and its involvement in the regulation of cell movements through remodeling the cytoskeleton architecture

“…Time-lapse imaging of dynamic microtubules al so revealed disorganized movements of the growing microtubule plus-ends in the cellular cortex region, including growth in a direction that is parallel to the cortex. The authors suggested that the functional mTOR-CLIP-170 interaction helps microtubules grow to the cellular cortex [46].…”