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.

Tanshinone I and simvastatin inhibit melanoma tumour cell growth by regulating poly (ADP ribose) polymerase 1 expression

“…In this study, the combination of tanshinone I and simvastatin improved the anti-tumour efficacy of simvastatin, but whether the combined effect of tanshinone I and other types of statins have the same effect requires further assessment. In a previous study, simvastatin increased the anti-tumour activity of paclitaxel (PTX) carried by lipid nanoemulsions (LDE), but not of the commercial PTX (not carried by LDE), possibly because of increased low-density lipoprotein receptor expression by statins that bind and internalize LDE-PTX ( 32 ). Thus, other potential mechanisms for the effects of the combination of simvastatin and tanshinone I on melanoma require further exploration.…”

Paclitaxel-loaded star-shaped copolymer nanoparticles for enhanced malignant melanoma chemotherapy against multidrug resistance

“… 10 , 11 Kretzer et al reported that lipid nanoemulsions which bind to low-density lipoprotein receptors could be used as carriers of PTX, and they decreased toxicity and increased the antitumor efficacy of PTX. 12 Battogtokh and Ko reported the PTX-loaded polymeric NPs showed sustained release and high cytotoxic efficacy comparable to that of free PTX on B16F10 melanoma cell lines, suggesting the PTX nanocarriers are potentially applicable to the treatment of melanoma. 13 …”

Nano Emulsions: A Novel Targeted Delivery of Cancer Therapeutics

“…However, the normal cells maintained a high level of viability. C57BL/6 mice with tumors administered acai oil Nano emulsions exhibited a significant reduction in tumor volume by 82% [52].…”