tretinoin and parthenolide

All-trans retinoic acid (ATRA) is one of the most useful drugs in the treatment for acute promyelocytic leukemia (APL), but its adverse effects, which include drug resistance and hypercalcemia are obstacles to achieving complete remission. Our previous study showed that some sesquiterpene lactones (STLs), i.e., helenalin (HE) and parthenolide (PA) but not sclareolide (SC), enhance ATRA-induced differentiation of HL-60 APL cells with no unexpected effects, but the precise mechanism on underlying this synergism is not yet fully understood. In this study, we investigated the distinctive transcriptional profile of cells treated with effective STL compounds, which were identified by comparing the profile with that of cells treated with SC. Genome-wide approaches using cDNA microarrays showed that co-treatment with the differentiation-enhancing STLs HE and PA maximized the transcriptional variation regulated by the suboptimal concentration of ATRA in HL-60 cells. Of the genes of interest, asparagine synthetase was remarkably downregulated by ATRA co-treated with either HE or PA, but not with SC. In an additional analysis for the role of asparagine synthetase, ATRA-mediated HL-60 cell differentiation was enhanced when asparagine in the culture media was depleted by an addition of L-asparaginase, indicating that downregulation of asparagine synthetase gene expression may be involved in the enhanced cell differentiation by STL compounds. These results provide useful insight into differentiation-inducing therapy in the treatment of leukemia.

Topics: Asparagine; Aspartate-Ammonia Ligase; Cell Differentiation; Culture Media; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Oligonucleotide Array Sequence Analysis; Receptors, Retinoic Acid; Sesquiterpenes; Sesquiterpenes, Guaiane; Tretinoin

Topics: Adenine; Adenine Nucleotides; Aminoglycosides; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arabinonucleosides; Carbazoles; Clofarabine; Cytarabine; Dasatinib; Daunorubicin; fms-Like Tyrosine Kinase 3; Furans; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Naphthalimides; Organophosphonates; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sesquiterpenes; Staurosporine; Stem Cell Transplantation; Thiazoles; Tretinoin

While many studies have documented tamoxifen's benefits as an adjuvant therapy in the treatment and prevention of recurrent breast cancer in estrogen receptor positive (ER+) breast carcinoma, this beneficial effect may decrease with long-term tamoxifen use. This experimental study was designed to compare the cytotoxic responses of ER+ primary breast cancer solid tumors derived from the MCF7 cell line to experimental therapeutics, including genistein, tamoxifen, all-trans retinoic acid (ATRA) and parthenolide in the presence and absence of exogenous beta-estradiol. The results of this study suggest that the growth inhibitory effects of tamoxifen, were dependent on beta-estradiol levels. In contrast, the cytotoxic effects of the isoflavone soy derivative, genistein, were observed to be independent of exogenous estrogen. Moreover, combined therapy using tamoxifen and genistein produced enhanced cytotoxic effects also independent of beta-estradiol levels. Additional studies involving the use of the novel agents all trans retinoic acid (ATRA) and parthenolide produced notable tumor responses and combined effects that were also estrogen-independent. Overall, these preclinical research findings suggest possible clinical applications suggesting that genistein might be a useful clinical adjuvant, particularly in post-menopausal women in whom breast cancer occurs more frequently. Moreover, this research suggests that combined treatment approaches involving the use of tamoxifen in conjunction with agents that inhibit NFkappaB pathway signaling, such as parthenolide and genistein, warrant further study.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estradiol; Female; Genistein; Humans; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Sesquiterpenes; Spheroids, Cellular; Tamoxifen; Tretinoin