Abstract 366: Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy

Abstract

High-grade Serous Ovarian Cancer (HGSOC) accounts for 68% of Ovarian Cancers (OvCas). It is a clinically aggressive neoplasm that even after treatment, a substantial proportion of advanced OvCas will develop resistance within 18 months. Thus, it is imperative to formulate anti-cancer agents that target cancer cells without affecting normal cells. The proposed study evaluated a novel method for targeted delivery of fisetin alone or combined with paclitaxel (PTX) at desired rates. We have used a natural polysaccharide (starch; FDA approved) as a core for planetary ball milled (PBM) nanoparticles which binds high-affinity folate receptors on OvCa cells via folate conjugated poly (ε-caprolactone)/poly (ethylene glycol) copolymer coating of the PBM nanoparticles. Treatment of OvCa cells (CAOV-3 and OVCAR-3) with PBM-NPs has shown its cytotoxic effect. The cell viability (MTT) assay was performed to determine the optimal IC50 values of fisetin, PTX alone, and in combination. These particles are rapidly internalized and induce significant cancer cell death at lower doses than unformulated fisetin or PTX. Importantly, negative controls showed that PBM nanoparticles without fisetin or paclitaxel have no toxic effects on OvCa cells. The immunofluorescence study confirmed the effectiveness of the combined drug; dead nuclei were found more within the cells treated by the combination than fisetin or PTX alone. The combined drug treatment was most effective in inhibiting proliferation and inducing apoptosis; accordingly, it showed noticeable increases in pro-apoptotic (BAX, BID), apoptotic (PARP, Caspase-3), and decreases in anti-apoptotic genes (BCL-XL and MCL-1) gene in a western blot and RT-PCR analysis. Taken together, we observed that the combination of PTX and fisetin resulted in significant cytotoxicity and apoptosis as compared to alone. Our results suggest that fisetin can be a potential agent in enhancing the efficacy of PTX in OvCa treatment. These finding highlights the promising role of natural bioactive compounds and provide the rationale for further transitional research. Citation Format: Melayshia McFadden, Santosh Kumar Singh, Rajesh Singh. Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 366.

Hexachlorobenzene as a differential modulator of the conventional and metronomic chemotherapy response in triple negative breast cancer cells

“…This could be due to the differences in the mechanism of action of both therapies. On one hand, in CT, PX must reach the cell cytoplasm to exert its stabilizing effect on microtubules [67,68], so it can be extruded by ABCG2 proteins [69,70] or metabolized by CYP proteins [65]. On the other hand, when PX and Carb are administered in a metronomic scheme, they exert a pro-apoptotic effect by the activation of mAchRs, which are present in the cell membrane [12].…”

Role of Fisetin in Selected Malignant Neoplasms in Women

“…The use of polymeric micelles (10~100 nm) reduced the release rate of fisetin (73% versus 93%), but also more effectively induced apoptosis in in vivo tests on OC heterotransplantation (SKOV3) in mice compared to those of free fisetin [12]. The nanodelivery approach has also proved beneficial for fisetin in combination with paclitaxel against OC cells (CAOV3, OVCAR3) [76]. Both components were placed inside nanoparticles formed by a naturally occurring polysaccharide (starch), coated with folate-conjugated poly(ε-caprolactone)/poly(ethylene glycol) copolymer [76].…”

“…The nanodelivery approach has also proved beneficial for fisetin in combination with paclitaxel against OC cells (CAOV3, OVCAR3) [76]. Both components were placed inside nanoparticles formed by a naturally occurring polysaccharide (starch), coated with folate-conjugated poly(ε-caprolactone)/poly(ethylene glycol) copolymer [76]. Such nanoparticles show an affinity to vitamin (folate) receptors rapidly accumulating inside OC cells and induce their death at much lower doses than with fisetin and paclitaxel used separately [76].…”

“…Both components were placed inside nanoparticles formed by a naturally occurring polysaccharide (starch), coated with folate-conjugated poly(ε-caprolactone)/poly(ethylene glycol) copolymer [76]. Such nanoparticles show an affinity to vitamin (folate) receptors rapidly accumulating inside OC cells and induce their death at much lower doses than with fisetin and paclitaxel used separately [76]. From a mechanistic point of view, the use of nanoparticles induced an increase in Bax and Bid, caspase 3, poly(ADP-ribose) polymerase (PARP) genes, as well as a decrease in anti-apoptotic genes (BcL-XL, MCL-1) [76].…”

“…Such nanoparticles show an affinity to vitamin (folate) receptors rapidly accumulating inside OC cells and induce their death at much lower doses than with fisetin and paclitaxel used separately [76]. From a mechanistic point of view, the use of nanoparticles induced an increase in Bax and Bid, caspase 3, poly(ADP-ribose) polymerase (PARP) genes, as well as a decrease in anti-apoptotic genes (BcL-XL, MCL-1) [76]. The use of nanotechnology to improve the therapeutic potential of fisetin has also been confirmed by other authors [16].…”