Ovarian cancer (OvCa) is a destructive malignancy due to difficulties in early detection and late advanced-stage diagnoses, leading to high morbidity and mortality rates for women. Currently, the quality treatment for OvCa includes tumor debulking surgery and intravenous platinum-based chemotherapy. However, numerous patients either succumb to the disease or undergo relapse due to drug resistance, such as to platinum drugs. There are several mechanisms that cause cancer cells’ resistance to chemotherapy, such as inactivation of the drug, alteration of the drug targets, enhancement of DNA repair of drug-induced damage, and multidrug resistance (MDR). Some targeted therapies, such as nanoparticles, and some non-targeted therapies, such as natural products, reverse MDR. Nanoparticle targeting can lead to the reversal of MDR by allowing direct access for agents to specific tumor sites. Natural products have many anti-cancer properties that adversely regulate the factors contributing to MDR. The present review displays the current problems in OvCa treatments that lead to resistance and proposes using nanotechnology and natural products to overcome drug resistance.

Since multiple reports established an association between diabetes mellitus and various cancers, emerging studies have surfaced to understand the effects of metformin as an anti-cancer agent. Although there was previous, but conflicting evidence, of a relationship between diabetes and ovarian cancer (OvCa), recent studies have supported this association. The mechanism of cancer development in patients with diabetes is likely to involve hyperglycemia, hyperinsulinemia, chronic inflammation, reactive oxygen species, regulation of cellular homeostasis, and activation of various pathways that lead to tumor cell proliferation. Preclinical evidence indicating that metformin, a medication commonly used to treat type 2 diabetes mellitus, may protect against OvCa. Metformin exerts anti-cancer properties by activating the MAPK pathway, inhibiting the PI3K/AKT/mTOR pathway, increasing tumor suppressor genes, inducing G2/M cycle arrest, and various other processes. Several studies have shown the efficacy of metformin as an adjunct with standard chemotherapeutic agents due to its synergistic effects on OvCa cells. This review highlights the epidemiologic evidence supporting a link between diabetes and OvCa, the fundamental molecular mechanism underlying carcinogenesis in patients with diabetes, the anti-cancer effects of metformin, and the need for further clinical investigations on combination therapies with metformin and standard chemotherapeutic agents for OvCa.

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.

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