Perifosine as potential anti-cancer agent inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells

Wang, Feng Ze; Fei, Hong Rong; Li, Xiao Qian; Ren-jiu, Shi; Wang, De Cai

doi:10.1007/s11010-011-0986-z

Cited by 13 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both H2009 and H1819 exhibited telomere shortening without a reduction in telomerase activity, suggesting that Perifosine may impair telomere maintenance in some backgrounds in a telomerase enzymatic activity independent manner, such as by regulating telomerase nuclear localization. AKT may modulate telomerase activity through a number of mechanisms, and Perifosine impacts pathways other than AKT, such as the p38 pathway [ 27 ], which may help explain some of the varying telomere biological responses to the drug. It is possible that Perifosine's other activities may be responsible for the observed telomere shortening.…”

Section: Discussionmentioning

confidence: 99%

Perifosine as a potential novel anti-telomerase therapy

et al. 2015

View full text Add to dashboard Cite

Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.

show abstract

Section: Discussionmentioning

confidence: 99%

Perifosine as a potential novel anti-telomerase therapy

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Several reports have demonstrated that TMV can activate Akt phosphorylation [12] , [39] . Recently, it was reported that the PI3K/Akt pathway affects EC motility and tube formation through the reorganization of actin cytoskeleton [40] , [41] . We for the first time showed that cell motility and tube formation were enhanced via the PI3K/Akt pathway in normal cells by the uptake of TMV.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis

et al. 2012

View full text Add to dashboard Cite

BackgroundIncreasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear.Methodology/Principal FindingsHere we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis.ConclusionWe for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment.

show abstract

“…The exact mechanism for the observed antitumor effect of perifosine in RCC remains unknown. Multiple mechanisms have been implicated that may mediate the antitumor effect of perifosine in preclinical studies, including the induction of apoptosis through both intrinsic and extrinsic pathways, cell cycle arrest, and antiangiogenesis in a variety of tumor types, [13][14][15][16][17][18][19] all of which are mediated through Akt rather than mTOR. The finding that PFS for patients in Groups A and B on the Perifosine 231 trial was nearly identical supports the belief that the mechanism of action of perifosine in RCC is distinct from that of the allosteric mTOR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor‐targeted therapy

Cho

Hutson

Samlowski

et al. 2012

Cancer

View full text Add to dashboard Cite

Background The clinical activity of allosteric mTOR inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of PI3-Kinase/Akt resulting from mTORC1 inhibition. Based on this rationale, two independent Phase II trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed prior VEGF-targeted therapy. Methods In Perifosine 228, 24 patients with advanced RCC were treated with perifosine (100 mg PO daily). Perifosine 231 enrolled two groups treated with daily perifosine (100 mg PO daily): Group A: No prior mTOR inhibitor, 32 patients; Group B: one prior mTOR inhibitor, 18 patients. Results In Perifosine 228, one patient achieved a partial response (PR) (ORR 4%; 95% CI [0.7, 20]) and 11 patients experienced a best response of stable disease (SD) (46%). Median PFS was 14.2 weeks (95% CI [7.7, 21.6]). In Perifosine 231, five patients experienced a PR (ORR 10% 95% CI [4.5, 22.2]) and 16 patients experienced a best response of SD (32%). Median PFS was 14 weeks [95% CI (12.9, 20.7)]. Overall, perifosine was well tolerated with very few grade 3 and 4 events. Most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue. Conclusion Although perifosine shows activity in patients with advanced RCC following failure of VEGF-targeted therapy, this activity is not superior to currently available second-line agents. Nonethelesss, perifosine may be worthy of further study in RCC in combination with other currently available therapies.

show abstract

Perifosine as potential anti-cancer agent inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells

Cited by 13 publications

References 21 publications

Perifosine as a potential novel anti-telomerase therapy

Perifosine as a potential novel anti-telomerase therapy

Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis

Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor‐targeted therapy

Contact Info

Product

Resources

About