griseofulvin and Breast-Neoplasms

Owing to the frequent observation of centrosome amplification in human cancers, cancer cells have a unique mechanism to suppress detrimental multipolar division by clustering multiple centrosomes into two functional spindle poles, known as centrosome clustering. This study investigated whether inhibition of centrosome clustering enhances the radiation sensitivity of breast cancer cells.. In this study, inhibition of centrosome clustering was examined by using various centrosome-declustering agents and KIFC1 siRNA in three breast cancer cell lines and two normal fibroblast cell lines. The combination effect of radiation and centrosome declustering was evaluated by cell viability, clonogenic, immunofluorescence assay.. This study showed that targeting centrosome clustering enhanced the efficacy of radiotherapy of breast cancer cells with less damage to normal cells. Ionizing radiation induced centrosome amplification in breast cancer cells, but not in normal fibroblast cells. Notably, we showed that centrosome declustering efficiently radiosensitized the centrosome-amplified breast cancer cells through induction of multipolar spindles but did not affect the viability of normal fibroblasts in response to irradiation. Furthermore, KIFC1 mediated the radiosensitivity of the centrosome-amplified breast cancer cells.. Our data provided the first evidence that centrosome clustering is a tumor-selective target for the improvement of radiotherapy in breast cancer cells.

Topics: Breast Neoplasms; Cell Division; Cell Line; Cell Line, Tumor; Cell Survival; Centrosome; Female; Fibroblasts; Griseofulvin; Humans; Kinesins; MCF-7 Cells; Phenanthrenes; Radiation-Sensitizing Agents; RNA Interference; Spindle Apparatus

Griseofulvin and 53 analogues of this compound have been tested against the pathogenic dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes as well as against the breast cancer cell line MDA-MB-231. The modifications to griseofulvin include the 4, 5, 6, 2', 3', and 4' positions. The SAR of the griseofulvin analogues toward the two fungi followed the same trend with the majority being less active than griseofulvin and none had more than twice the potency of the parent compound. A comparison of the antifungal and the anticancer SAR revealed distinct differences, as the majority of analogues showed increased activity against the cancer cell line MDA-MB-231, highlighted by 2'-benzyloxy-2'-demethoxy-griseofulvin, which showed low activity against both fungi but was among the most potent compounds against MDA-MB-231 cancer cells. Tubulin has been proposed as the target of griseofulvin in both fungal and mammalian cells, but the differences revealed by this SAR study strongly suggest that the mode-of-action of the compound class toward fungi and mammalian cancer cells is different.

Topics: Antifungal Agents; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Griseofulvin; Humans; Mycology; Structure-Activity Relationship; Trichophyton

Griseofulvin, an antifungal drug, has recently been shown to inhibit proliferation of various types of cancer cells and to inhibit tumor growth in athymic mice. Due to its low toxicity, griseofulvin has drawn considerable attention for its potential use in cancer chemotherapy. This work aims to understand how griseofulvin suppresses microtubule dynamics in living cells and sought to elucidate the antimitotic and antiproliferative action of the drug.. The effects of griseofulvin on the dynamics of individual microtubules in live MCF-7 cells were measured by confocal microscopy. Immunofluorescence microscopy, western blotting and flow cytometry were used to analyze the effects of griseofulvin on spindle microtubule organization, cell cycle progression and apoptosis. Further, interactions of purified tubulin with griseofulvin were studied in vitro by spectrophotometry and spectrofluorimetry. Docking analysis was performed using autodock4 and LigandFit module of Discovery Studio 2.1.. Griseofulvin strongly suppressed the dynamic instability of individual microtubules in live MCF-7 cells by reducing the rate and extent of the growing and shortening phases. At or near half-maximal proliferation inhibitory concentration, griseofulvin dampened the dynamicity of microtubules in MCF-7 cells without significantly disrupting the microtubule network. Griseofulvin-induced mitotic arrest was associated with several mitotic abnormalities like misaligned chromosomes, multipolar spindles, misegregated chromosomes resulting in cells containing fragmented nuclei. These fragmented nuclei were found to contain increased concentration of p53. Using both computational and experimental approaches, we provided evidence suggesting that griseofulvin binds to tubulin in two different sites; one site overlaps with the paclitaxel binding site while the second site is located at the alphabeta intra-dimer interface. In combination studies, griseofulvin and vinblastine were found to exert synergistic effects against MCF-7 cell proliferation.. The study provided evidence suggesting that griseofulvin shares its binding site in tubulin with paclitaxel and kinetically suppresses microtubule dynamics in a similar manner. The results revealed the antimitotic mechanism of action of griseofulvin and provided evidence suggesting that griseofulvin alone and/or in combination with vinblastine may have promising role in breast cancer chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Binding Sites; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromosome Segregation; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Drug Synergism; Female; Flow Cytometry; Fluorescent Antibody Technique; Griseofulvin; Humans; Kinetochores; Microscopy, Confocal; Microtubules; Models, Molecular; Molecular Structure; Protein Conformation; Spectrometry, Fluorescence; Spectrophotometry; Time Factors; Transfection; Tubulin; Tubulin Modulators; Tumor Suppressor Protein p53; Vinblastine

Risk of breast cancer in women was assessed for eight pharmaceuticals that produce mammary tumors in experimental animals, using nested case-control analyses in two cohorts with prescription records in a comprehensive medical care program. The two cohorts were: (1) earlier cohort: 78,118 female members who received prescriptions in 1969-1973, of whom 2,467 developed breast cancer, and (2) later cohort: 3,289,408 female members who received prescriptions in 1994-2006 of whom 24,528 developed breast cancer. Longest follow-up was until June 30, 2006. Ten randomly selected concurrent control women were age-matched to almost every case. Relative risks were estimated by conditional logistic regression. Case ascertainment was lagged by 2 years, or unlagged and subdivided by number of prescriptions received. Some analyses were controlled for hormone use and sensitivity analyses were conducted to estimate the effects of uncontrolled confounding. In the later cohort furosemide, and metronidazole showed statistically significant but very small increases in relative risk (ranging from 1.07 to 1.13). Of these, only furosemide showed increased risk in the earlier cohort: 2-year lag relative risk 1.66 (95% confidence interval 1.23-2.24) or as low as 0.97, assuming uncontrolled positive confounding. Griseofulvin showed significant increases in the later cohort: relative risk for three or more prescriptions 1.48 (1.08-2.03) or as low as 1.23 assuming uncontrolled positive confounding and non-significant increases were noted in the earlier cohort. Our findings are limited by their inconsistency across the two cohorts and our inability to directly control for most established breast cancer risk factors. Although inconclusive, our findings suggest a need for more research on furosemide and griseofulvin.

Topics: Adult; Aged; Antifungal Agents; Antiprotozoal Agents; Breast Neoplasms; Case-Control Studies; Diuretics; Drug-Related Side Effects and Adverse Reactions; Female; Furosemide; Griseofulvin; Humans; Metronidazole; Middle Aged; Pharmacoepidemiology; Risk Factors; SEER Program; Sensitivity and Specificity

Topics: Animals; Antifungal Agents; Artemia; Benzaldehydes; Breast Neoplasms; HT29 Cells; Humans; Lung Neoplasms; Mexico; Plant Stems; Seeds; Trees