Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

Abstract

Fluvastatin (FLV) is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor often used to lower total and low-density lipoprotein (LDL) cholesterol and for the prevention of adverse cardiovascular events. This drug as well as melittin (MEL), the major component of honeybee venom (Apis mellifera), has shown antineoplastic activity, then representing promising approaches for cancer therapy. However, adverse effects related to the use of FLV and MEL have been reported and very few studies have been carried out to obtain an optimized formulation allowing for combining the two drugs and then maximizing the anticancer activity, then minimizing the needed dosage. In the present study, an optimized formulation in terms of minimized particle size and maximized zeta potential was investigated for its cytotoxic potential in human OVCAR3 ovarian cancer cells. FLV-MEL nano-conjugates, containing a sub-toxic concentration of drug, demonstrated an improved cytotoxic potential (IC50 = 2.5 µM), about 18-fold lower, compared to the free drug (IC50 = 45.7 µM). Cell cycle analysis studies demonstrated the significant inhibition of the OVCAR3 cells proliferation exerted by FLV-MEL nano-conjugates compared to all the other treatments, with a higher percentage of cells accumulating on G2/M and pre-G1 phases, paralleled by lower percentage of cells in G0/G1 and S phases. The synergistic antineoplastic activity of FLV and MEL combined in the optimized formula was also showed by the marked pronecrotic and pro-apoptotic activities, the latter mediated by the modulation of BAX/BCL-2 ratio in favor of BAX. Our optimized FLV-MEL formulation might therefore represents a novel path for the development of specific and more effective antineoplastic drugs directed against ovarian cancer.

RETRACTED ARTICLE: Fluvastatin-Loaded Emulsomes Exhibit Improved Cytotoxic and Apoptosis in Prostate Cancer Cells

“…This observation is asserted by X 2 positive coefficient in the coded equation. The increase in the size of FLV-EMLs with the PC concentration increase is possibly related to increased number of the multiple bilayers formed during EML preparation [22,42]. On the contrary, the particle size was decreased signifi- cantly at higher drug concentrations (Fig.…”

Ceftriaxone and Melittin Synergistically Promote Wound Healing in Diabetic Rats

“…For the preparation of the ion-pairing nanocomplexes, CTX and MEL were formulated with a 1:2 ratio. This ratio between the two components was selected based on our preliminary laboratory investigation as well as on a recently published work [ 22 ]. CTX and MEL were dissolved separately in deionized water.…”

“…All analyses were performed using GraphPad Prism software ® [ 30 ], version 8.0 (GraphPad, La Jolla, CA, USA). Only two-tailed p values < 0.05 were considered statistically significant [ 22 , 31 ].…”

Piceatannol-Loaded Bilosome-Stabilized Zein Protein Exhibits Enhanced Cytostatic and Apoptotic Activities in Lung Cancer Cells

“…The prepared cells were then incubated with various concentrations of plain-BZ, PIC, or PIC-BZ (dispersed in the cell culture medium) in a CO 2 incubator at logarithmic intervals of 48 h at 37 °C. In order to determine the IC 50 values, we employed a MTT assay method as previously described [ 49 ].…”