Back to Search
Start Over
Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways.
- Source :
-
PloS one [PLoS One] 2015 Dec 04; Vol. 10 (12), pp. e0143830. Date of Electronic Publication: 2015 Dec 04 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- Background: The mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways.<br />Methods: Therefore, we tested the effect of lovastatin--known to inhibit both ERK and AKT signaling--and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines.<br />Results: Lovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P ≤ 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P ≤ 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect.<br />Conclusion: In summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable reactions of the different cell lines highlight the necessity to understand the unique molecular aberrations in any tumor. Nevertheless, this combination seems worthy of being tested in vivo.
- Subjects :
- Animals
Drug Synergism
ErbB Receptors genetics
ErbB Receptors metabolism
Hep G2 Cells
Humans
Mice
Mice, Knockout
Neoplasms genetics
Neoplasms metabolism
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Ribosomal Protein S6 Kinases, 70-kDa genetics
Ribosomal Protein S6 Kinases, 70-kDa metabolism
Everolimus agonists
Everolimus pharmacology
Lovastatin agonists
Lovastatin pharmacology
MAP Kinase Signaling System drug effects
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26636335
- Full Text :
- https://doi.org/10.1371/journal.pone.0143830