Search

• Chondrosarcoma stem cells (ChSCs) are radioresistant and are suppressed by miR-34. • mTOR inhibition by Rapamycin targets ChSCs via FOXO3 and miR-34. • Combination of carbon-ion therapy with mTOR inhibitors effectively controls ChSCs. High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours. In this study, we investigated whether HT exclusively interferes with HR by analysing thermal radiosensitisation of BRCA2-proficient and deficient cells. After elucidating the equitoxicity of PARP1-ion BRCA2-proficient and deficient cells, we studied the cell survival, apoptosis, DNA damage (γ-H2AX foci and comet assay) and cell cycle distribution after different treatments. PARP1-isensitivity strongly depends on the BRCA2 status. BRCA2-proficient and deficient cells are radiosensitised by HT, indicating that HT does not exclusively act by inhibition of HR. In all cell lines, the addition of HT to radiotherapy and PARP1-iresulted in the lowest cell survival, the highest levels of DNA damage and apoptotic levels compared to duo-modality treatments. Concluding, HT not only inhibits HR, but also has the capability of radiosensitising BRCA2-deficient cells. Thus, in case of BRCA2-mutation carriers, combining HT with PARP1-imay boost the treatment efficacy. This combination therapy would be effective for all patients with PARP1-iregardless of their BRCA status. [ABSTRACT FROM PUBLISHER]

Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cellsin vitrowhen administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 μM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P< 0.05) reducing the capacity of MCF-7 cells to form colonies. Even at 24 h, 38 foci/cell were observed in samples that were given the combined treatment, suggesting the cells' inability in repairing the damage. Also, increased apoptosis in EA+ 2Gy (50%) and EA+ 4 Gy (62%)-treated cells was observed in the the sub-G1 phase of the cell cycle. A 6.2-fold decrease in the mitochondrial membrane potential was observed in the combined treatment of EA and IR that facilitated the upregulation of pro-apopttotic Bax and downregulation of Bcl-2, pushing the MCF-7 cells to undergo an apoptotic cell death. It is suggested that EA may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity and reducing the normal cell damage caused by irradiation. [ABSTRACT FROM PUBLISHER]

This study evaluates the potential of ellagic acid (EA) as an enhancer of radiation-induced apoptosis in cancer cells. HeLa cells treated with EA and gamma radiation showed increased superoxide generation, upregulated p53 protein expression, and decreased antioxidant enzymes. We also found that EA and radiation enhance capase-3 activity via oxidative stress, increased intracellular calcium levels, and phospholipase C and cause a drop in mitochondrial potential. These results might provide a basis for prominent reduction of cancer cell using EA as an adjunct to radiotherapy and an opportunity to lower the toxic radiation doses to improve the quality of life. [ABSTRACT FROM AUTHOR]

Plants are a rich source for bioactive compounds. However, plant extracts can harbor a mixture of bioactive molecules that promote divergent phenotypes and potentially have confounding effects in bioassays. Even with further purification and identification, target deconvolution can be challenging. Corynoline and acetylcorynoline, are phytochemicals that were previously isolated through a screen for compounds able to induce mitotic arrest and polyploidy in oncogene expressing retinal pigment epithelial (RPE) cells. Here, we shed light on the mechanism by which these phytochemicals can attack human cancer cells. Mitotic arrest was coincident to the induction of centrosome amplification and declustering, causing multi-polar spindle formation. Corynoline was demonstrated to have true centrosome declustering activity in a model where A549 cells were chemically induced to have more than a regular complement of centrosomes. Corynoline could inhibit the centrosome clustering required for pseudo-bipolar spindle formation in these cells. The activity of AURKB, but not AURKA or polo-like kinase 4, was diminished by corynoline. It only partially inhibited AURKB, so it may be a partial antagonist or corynoline may work upstream on an unknown regulator of AURKB activity or localization. Nonetheless, corynoline and acetylcorynoline inhibited the viability of a variety of human cancer derived cell lines. These phytochemicals could serve as prototypes for a next-generation analog with improved potency, selectivity or in vivo bioavailability. Such an analog could be useful as a non-toxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired. [Display omitted] • Corynoline, a benzophenanthridine alkaloid phytochemical, disrupts cell division. • Mitotic arrest, apoptosis and polyploidy are coincident with centrosome defects. • Corynoline definitively induces centrosome declustering in cancer cells. • AURKB activity, but not AURKA, is diminished by corynoline treatment. [ABSTRACT FROM AUTHOR]