Identification of the Genes Involved in Enhanced Fenretinide-Induced Apoptosis by Parthenolide in Human Hepatoma Cells

Abstract

Fenretinide (N-4-hydroxyphenyl retinamide, 4HPR) is a synthetic anticancer retinoid that is a well-known apoptosisinducing agent. Recently, we observed that the apoptosis induced by fenretinide could be effectively enhanced in hepatoma cells by a concomitant treatment with parthenolide, which is a known inhibitor of nuclear factor-n nB (NF-n nB). Furthermore, treatment with fenretinide triggered the activation of NF-n nB during apoptosis, which could be substantially inhibited by parthenolide, suggesting that NF-n nB activation during fenretinide-induced apoptosis has an antiapoptotic effect. This study investigated the molecular mechanism of this apoptotic potentiation by NF-n nB inhibition. The genes involved in the enhanced fenretinide-induced apoptosis by parthenolide were identified using the differential display-PCR method and subsequent Northern blot or semiquantitative reverse transcriptase PCR analysis. This study identified 35 apoptosis-related genes including 12 unknown genes that were either up-or down-regulated by parthenolide. Interestingly, one up-regulated gene (HA1A2) was isolated and cloned from the liver cDNA, and was found to be identical to ANKRD1, which is also referred to as the CARP gene. Compared with controls treated with an empty vector or with antisense cDNA, the ectopic expression of ANKRD1 led to reduced colony formation and to enhanced apoptotic cell death in hepatoma cells. These results suggest that ANKRD1 and the other genes, whose expressions were substantially modulated by the parthenolide-mediated inhibition of NF-n nB activation, play roles in the enhanced drug-induced apoptosis. In addition, this study suggests that those identified genes may be useful in anticancer strategies against hepatoma. (Cancer Res 2005; 65(7): 2804-14)

Ankyrin Repeat Domain 1, ANKRD1, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer

“…In addition, ectopic expression of ANKRD1 in rat embryonic heart cells decreased susceptibility to apoptosis (33), a situation which would be consistent with decreased susceptibility to cisplatin observed with increasing ANKRD1 expression in this study. In contrast, however, ANKRD1 was up-regulated in hepatoma cells in response to fenretinide, an anticancer retinoid, and in this context ANKRD1 has been suggested to be proapoptotic (28). In our cell line model, the sensitive mutant cell line that had lost expression of Ankrd1 had at least three defects related to cisplatin sensitivity: increased drug influx, decreased glutathione levels, and defective DNA repair (34).…”

“…We found ANKRD1 to be expressed in 5 of 9 ovarian cancer cell lines, in 1 of 5 human breast cancer cell lines, and in the majority of serous ovarian adenocarcinomas tested. ANKRD1 has been reported to be expressed in rhabdomyosarcomas (27) and in hepatoma cell lines (28), but to our knowledge this is first report of ANKRD1 expression in human ovarian and breast cancer cells. Moreover, there are few published studies of ANKRD1 expression in response to chemotherapeutic agents, and the data that are available are contradictory.…”

“…In vivo studies in pigs, however, have shown that long-term exposure to high levels of doxorubicin resulted in increased ANKRD1 expression (30). Parthenolide, an NF-nB inhibitor that has been suggested for combinational chemotherapy to overcome drug resistance (31), also increased expression of ANKRD1 in hepatoma cell lines (28), but the underlying mechanisms, potential interactions between ANKRD1 and NF-nB, and the implications for response to therapy are far from clear.…”

The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro

“…Recent studies have identified PTL as a potential agent for the treatment of myeloid leukemias, 19 hepatomas 16,17 and cholangiocarcinoma. 18 The data here show that PTL shows a level of cytotoxicity towards CLL cells comparable to or greater than that observed in these earlier studies.…”

“…14 The sesquiterpene lactone parthenolide (PTL) has been widely used in traditional medicine for the treatment of migraines and inflammation. 15 This compound has recently been shown to induce apoptosis of hepatoma 16,17 and cholangiocarcinoma 18 cell lines and of primary acute and chronic myeloid leukemia cells 19 in vitro, with IC 50 values varying between 5 and 20 mM. The killing of hepatoma 16 and myeloid leukemia 19 cells was dependent on the PTL-induced generation of reactive oxygen species (ROS).…”