In vitro and in vivo therapeutic approach for a small cell carcinoma of the ovary hypercalcaemic type using a SCCOHT-1 cellular model

BACKGROUND: The small cell ovarian carcinoma of the hypercalcemic type (SCCOHT) which preferably affects young women during regenerative age represents a rare and aggressive form of ovarian tumors with poor prognosis and lacks an efficient therapy. METHODS AND RESULTS: In vitro chemotherapy testing in a fluorescence assay using a recently developed cellular model from a recurrent SCCOHT revealed sensitivity for certain epothilones, methotrexate and topotecan whereas little if any cytotoxicity was observed with other chemotherapeutics including platin-based compounds. In particular, epothilone B demonstrated a high sensitivity in contrast to ixabepilone with only little detectable effects. Western blot and cell cycle analysis revealed that the epothilone B sensitivity was associated with increased Ser(15) phosphorylation of p53, a significant G(1) and G(2) cell cycle accumulation and subsequent cell death in subG(1) phase. Moreover, tubulinβ3 expression in SMARCA4/BRG1-defective SCCOHT-1 in contrast to other ovarian cancer cells was also affected during chemotherapy treatment. Increased extracellular Ca(2+) levels further enhanced the epothilone B cytotoxicity in SCCOHT-1 cells. These in vitro effects were also confirmed in vivo in NOD/scid mouse xenografts demonstrating an attenuated tumor growth in epothilone B / Ca(2+)-treated mice. After 4d of subsequent treatment, the tumor sizes were reduced by about 90% as compared to continuously growing control tumors. In parallel, a hypercalcemia in control tumor-carrying mice was reverted to normal serum Ca(2+) levels after epothilone B / Ca(2+) therapy. CONCLUSIONS: Taken together, these data demonstrated anti-tumorigenic effects of epothilone B / Ca(2+) in SCCOHT providing a focused therapeutic approach against this rare disease and arising recurrent tumors.