Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice.

Abstract

PURPOSE:

Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX).

MATERIALS AND METHODS:

B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days.

RESULTS:

Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression.

CONCLUSION:

Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX.

• Authors: Iara F Kretzer, Durvanei A Maria, Maria C Guido, Thaís C Contente, Raul C Maranhão
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 11 Pg. 885-904 ( 2016) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 27022257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, LDL
• Lipids
• Receptors, LDL
• Simvastatin
• Paclitaxel

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Cholesterol, LDL (metabolism)
• Drug Synergism
• Female
• Immunoenzyme Techniques
• Injections, Intraperitoneal
• Lipids (chemistry)
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Paclitaxel (administration & dosage)
• Receptors, LDL (metabolism)
• Simvastatin (administration & dosage)
• Tumor Cells, Cultured