The Potential of Novel Lipid Agents for the Treatment of Chemotherapy-Resistant Human Epithelial Ovarian Cancer

Abstract

Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune modulators. Our preclinical studies highlight a novel tool to combat chemotherapy-resistant human EOC. Glycosylated antitumor ether lipids (GAELs) are synthetic glycerolipids capable of killing established human epithelial cell lines from a wide variety of human cancers, including EOC cell lines representative of different EOC histotypes. Importantly, GAELs kill high-grade serous ovarian cancer (HGSOC) cells isolated from the ascites of chemotherapy-sensitive and chemotherapy-resistant patients grown as monolayers of spheroid cultures. In addition, GAELs were well tolerated by experimental animals (mice) and were capable of reducing tumor burden and blocking ascites formation in an OVCAR-3 xenograft model. Overall, GAELs show great promise as adjuvant therapy for EOC patients with or without chemotherapy resistance.

Keywords: chemotherapy resistance; epithelial ovarian cancer (EOC); glycosylated antitumor ether lipid; methuosis.

Figure 1

Different classes of antitumor ether lipids (AELs); alkyllysophospholipids (ALP), alkylphospholipids (APL), and glycosylated antitumor ether lipids (GAEL).

Figure 2

Structural evolution of GAEL prototypes. 1 = α-GLN, 2 = β-GLN; 3 and 4 are C-glycosidic analogs; 5 and 6 incorporate a second amino group at the 6 position; dibasic analogs 7 and 8 with L-glucose; 9 = 3-amino-1-O-hexadecyloxy-2R-(O–α-L-Rhamnopyranosyl)-sn-glycerol (L-Rham).

Figure 3

GAEL structure–activity relationship map. Data compiled from references [50,52,88,90,91,92,94].

Figure 4

HGSOC cell viability after L-Rham treatment. (A). Dose response of established HGSOC cell lines treated with L-Rham for 48 h. Cells were grown as adherent monolayers. For (A,B), cells were grown as adherent monolayers, and for (C,D) cells, they were grown as non-adherent cell aggregates or spheres (depending on the individual sample). The dashed lines indicate 50% cell viability. Asterisks (*) indicate significant differences from vehicle-treated cells [* < 0.05, ** < 0.01, *** < 0.001, **** < 0.0001]; 2-way ANOVA with multiple comparisons was used to assess significance. (B). Dose response of chemosensitive and chemoresistant HGSOC patient samples treated with L-Rham for 48 h. (C). Dose response of chemosensitive HGSOC patient samples treated with L-Rham for 48 h. (D). Dose response of chemoresistant HGSOC patient samples treated with L-Rham for 48 h. Modified from reference [49], with permission.

Figure 5

HGSOC cell viability after L-Rham treatment. Alteration in spheroid morphology in response to increasing doses of L-Rham after 48 h. Solid bar = 100 µm. Modified from reference [49], with permission.

Figure 6

L-Rham phenotypic response. Development of phase-lucent cytoplasmic vesicles (arrowheads) 24 h after initial exposure to L-Rham. Primary EOC230 cells were isolated from HGSOC patient ascites. Vehicle = 0.9% saline. Solid bar = 100 µm.

Figure 7

Primary patient EOC cell L-Rham sensitivity. Dose response to L-Rham for primary patient samples isolated from the ascites of patients representing each major EOC histotype. Vehicle = 0.9% saline. Cells were grown as a 2D adherent monolayer and exposed to L-Rham for 48 hours. The dashed lines indicate 50% cell viability. Data were obtained from 3 independent experiments with 6 data points per experiment. Vertical lines indicate standard deviation, and asterisks (*) indicate significant difference from vehicle-treated cells, [* < 0.05, ** < 0.01, *** < 0.001]; Kruskal–Wallis test with Dunn’s multiple comparisons per group was used to assess significance.