FU-OV-1

Identification of Foods that Affect the Anti-Cancer Activity of Pitavastatin in Cells

Statins block mevalonate synthesis, crucial for modifying small GTPase oncogenes. Previously, Jawad et al. showed geranylgeraniol can counteract statins in cell cultures, and pitavastatin reduces ovarian cancer tumors in mice on geranylgeraniol-free diets. Thus, dietary geranylgeraniol might limit statin effectiveness in cancer trials. They identified foods affecting pitavastatin's cytotoxicity in ovarian cancer cells.

Pitavastatin's effect on Ovcar-4 cells was first confirmed (IC₅₀ = 5.2±1.20 µM). Prior findings showed geranylgeraniol and mevalonate, but not farnesol, reduce pitavastatin's cytotoxicity. Further testing revealed that dolichol, coenzyme Q10, and cholesterol did not alter pitavastatin's effect. As expected, geranylgeraniol countered pitavastatin's inhibition. Using Fuov-1 cells, similar patterns appeared with mevalonate pathway metabolites. Next, organic solvent extracts from various foods were tested for geranylgeraniol content. Extracts from oils like corn, sunflower, and grape seed reduced pitavastatin's activity but rape seed oil did not (Fig. 1A). Among fruits and vegetables, beans and cherries partly restored cell growth despite pitavastatin, while lettuce extract significantly suppressed pitavastatin but also stimulated cell growth alone (Fig. 1B). Most carbohydrate-rich food extracts didn't affect pitavastatin, except oats (Fig. 1C). Other foods, including pecan nuts, boiled eggs, and a pasta sauce, suppressed pitavastatin, though some were toxic alone (Fig. 1D). Results were consistent when retested on Fuov-1 cells with selected extracts (Fig. 2).

Fig. 1. Effect of food extracts on the activity of pitavastatin in Ovcar-4 cells (Jawad M J, Ibrahim S, et al., 2022).

Fig. 2. Effect of food extracts on the activity of pitavastatin in Fuov-1 cells. Effect of extracts from various foodstuffs on the cytotoxic activity of pitavastatin was assessed in Ovcar-4 cells (Jawad M J, Ibrahim S, et al., 2022).

GAB2^High Ovarian Cancer Cell Lines are Selectively Sensitive to SHP2 Inhibition

High-grade serous ovarian cancers (HGSOCs) account for the majority of ovarian cancer deaths and pose treatment challenges due to frequent recurrences and platinum resistance. GAB2 overexpression, linked with poor cancer prognoses, facilitates oncogenic signaling in RAS-ERK and PI3K-AKT pathways. To address therapeutic gaps in HGSOCs, Sun et al. employed in vitro and in vivo methods to test dual inhibition of SHP2 and PI3K in GAB2-high ovarian cancer.

They studied if ovarian cancer cell lines with GAB2 amplification/overexpression depend on SHP2 for growth. From CCLE data on 51 cell lines, they identified 9 serous ovarian cancer cell lines with different GAB2 levels. Using PCR and immunoblotting, they found two cell lines (OVCAR3 and JHOS4) with GAB2 amplification and high GAB2 mRNA/protein, two (FUOV1 and IGROV1) with high GAB2 without gene changes, and five (HEYA8, OVCAR5, OV90, OVCAR4, SKOV3) with low GAB2 levels (Fig. 3B and 3C). After SHP099 treatment, the 4 cell lines with high GAB2 showed more sensitivity than the 5 low GAB2 cell lines (Fig. 3D). The were as sensitive or more sensitive than HCC827 lung cancer cells with EGFR mutation to SHP099. SHP099 at 5 μM stopped growth in the 4 high GAB2 lines but not in 2 low GAB2 lines (Fig. 3E and 3F), linked to decreased p-ERK1/2, not p-AKT, levels (Fig. 3G). This suggests SHP2 is necessary for GAB2High ovarian cancer cell growth and ERK1/2 activation.

Fig. 3. GAB2^High ovarian cancer cell lines are selectively dependent on SHP2 for proliferation and survival (Sun B, Jensen N R, et al., 2019).