Sesquiterpene drugs as potential treatment for hepatocellular carcinoma (HCC): Preclinical evaluation of parthenolide administered via transarterial chemoembolization in a rat HCC tumor model.

摘要

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer--related deaths and claims ∼750,000 lives yearly in the world. This high mortality and prevalence make HCC a prominent malignancy requiring therapeutic intervention. Parthenolide (PTL), a natural sesquiterpene, has been shown to exhibit potent anticancer and anti-inflammatory activities in many in vitro and in vivo studies, which includes in work carried out in our own laboratories. However, the oral bioavailability of PTL is very limited due to its poor water solubility, precluding its effectiveness as a clinical agent for treatment of hepatocellular carcinoma (HCC). The central hypothesis of this dissertation is that PTL will effectively inhibit HCC tumor growth with tolerable systemic side effects in an established rat HCC model when administered via transarterial chemoembolization (TACE).;The in vitro cytotoxicity profiles for PTL and dimethylamino-parthenolide (DMAPT) against different HCC tumor cell lines and normal rat liver parenchyma cells have been initially established, utilizing cell proliferation and colony formation assays, as well as lactate dehydrogenase activity assay. The results demonstrated that PTL and DMAPT did not exhibit cytotoxicity against normal rat hepatocytes but did produce antiproliferative activity against liver tumor cells. In vivo studies PTL in lipiodol solution (80mM) was delivered via TACE utilizing a rat HCC tumor model. Twenty-four HCC tumor-bearing rats were randomly divided into three groups (eight rats per group): i.e. saline group, lipiodol group, and PTL/lipiodol group. The average tumor growth in the PTL/lipiodol group was significantly less than in the other two groups at 9 days following PTL treatment. Whole body weight and blood measurements of liver function did not show significant signs of toxicity.;The stability and solubility profile of PTL in lipiodol and other biological fluids was determined utilizing a validated LC-DAD analytical method. In addition, an LC-MS/MS analytical method was developed to determine PTL concentrations in rat plasma on days 3, 6 and 9 following the administration of PTL via TACE, and to determine the concentration of PTL in rat liver homogenate on day 9 after the administration of PTL via TACE. The PTL concentrations in all rat samples were found to be below the lower limit of detection by LC-MS/MS analysis.;It is concluded that the administration of PTL in lipiodol via TACE constitutes an effective anticancer treatment for the rat HCC model. The lack of toxicity associated with this treatment appears to be very promising and warrants further development of this delivery approach for treatment of HCC patients.