Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism

Abstract

Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here, we have assessed the effect of pantethine on tumor growth and metabolism using magnetic resonance imaging and high-resolution proton magnetic resonance spectroscopy (MRS) in a model of ovarian cancer. To evaluate treatment strategies, it is important to use models that closely mimic tumor growth in humans. Therefore, we used an orthotopic model of ovarian cancer where a piece of tumor tissue, derived from an ovarian tumor xenograft, is engrafted directly onto the ovary of female mice, to maintain the tumor physiological environment. Treatment with pantethine, the precursor of vitamin B5 and active moiety of coenzyme A, was started when tumors were ~100 mm3 and consisted of a daily i.p. injection of 750 mg/kg in saline. Under these conditions, no side effects were observed. High-resolution 1H MRS was performed on treated and control tumor extracts. A dual-phase extraction method based on methanol/chloroform/water was used to obtain lipid and water-soluble fractions from the tumors. We also investigated effects on metastases and ascites formation. Pantethine treatment resulted in slower tumor progression, decreased levels of phosphocholine and phosphatidylcholine, and reduced metastases and ascites occurrence. In conclusion, pantethine represents a novel potential, well-tolerated, therapeutic tool in patients with ovarian cancer. Further in vivo preclinical studies are needed to confirm the beneficial role of pantethine and to better understand its mechanism of action.

Pantethine Down-Regulates Leukocyte Recruitment and Inflammatory Parameters in a Mouse Model of Allergic Airway Inflammation

“…It has been already used in humans against various pathologies, with no detectable adverse effects [ 20 ]. Based on a previous work showing that it drastically attenuates the diffusion of cancer metastases [ 21 ], the present report confirms that pantethine inhibits pathogenic cell migration, meaning that it could provide a distinct appropriate therapy for allergic asthma.…”

Ascites Volumes and the Ovarian Cancer Microenvironment

“…ID8-Defb29 Vegf cells were grown in RPMI 1640 medium with 10% fetal bovine serum, and cultured under standard cell culture incubator conditions at 37°C in a humidified atmosphere containing 5% CO 2 . Cells were orthotopically implanted in C57BL/6J mice using a two-step process as previously described (10, 11). First, subcutaneous tumors were generated by inoculating a cell suspension of 2 × 10 6 ID8-Defb29 Vegf cells in 0.05 ml of Hanks balanced salt solution in the flank of C57BL/6J female mice.…”

“…However, with this procedure, most cell lines do not form solid tumors. Instead, here we performed microsurgical orthotopic implantation of ovarian cancer tissue within the ovary of C57BL/6J mice (10). Tumors reached ~300 mm 3 in 4–6 weeks.…”

Metabolomic characterization of experimental ovarian cancer ascitic fluid

“…Our orthotopic implantation model consisted of a two-step process (Penet et al 2016). We first generated subcutaneous tumors by inoculating a cell suspension of 2 × 10 6 OVCAR3 or ID8-VEGF-Defb29 cells in 0.05 ml of Hanks balanced salt solution in the flank of SCID or C57BL/6 female mice.…”