Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of
ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in
ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered
paclitaxel treatment approach in nude mice inoculated with
ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of
paclitaxel in mice 7 days after subcutaneous
transplantation of the HEY
ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive
paclitaxel. In the second approach, mice were administered once weekly with
paclitaxel and/or a daily dose of the JAK2-specific inhibitor,
CYT387, over 4 weeks. Mice receiving
paclitaxel only demonstrated a significant decrease in
tumor volume compared to control mice. At the molecular level, mouse
tumors remaining after
paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control
tumors. The addition of
CYT387 with
paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller
tumors in mice administered
CYT387 in addition to
paclitaxel, compared to the control group and the group of mice receiving
paclitaxel only. These data suggest that the systemic administration of
paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving
cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor
CYT387, leading to a significantly smaller
tumor burden. These novel findings have the potential for the development of CSC-targeted
therapy to improve the treatment outcomes of
ovarian cancer patients.