Effect of HIF-1 modulation on the response of two- and three-dimensional cultures of human colon cancer cells to 5-fluorouracil.

Tumour hypoxia represents a major obstacle to the success of radiotherapy and chemotherapy. The discovery that the hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular response to low oxygen led to the concept that inhibiting HIF-1 activity may sensitise hypoxic cancer cells to radiation and cytotoxic drugs. In the present study we investigate the effects of HIF-1 modulation on the response of the human colon adenocarcinoma cell line HCT116 to 5-fluorouracil (5FU). Increasing HIF-1 activity, either by exposing cells to hypoxia or by forced expression of a degradation-resistant form of HIF-1alpha, results in poor cell response to 5FU; conversely, knockdown of HIF-1alpha by RNA interference prevents hypoxia-induced resistance to 5FU. PMX290, a thioredoxin-1 inhibitor, significantly inhibits HIF-1 activity and concomitantly sensitises hypoxic cells to 5FU. These results were confirmed in HCT116 cells grown as three-dimensional spheroids, a model that more closely reproduces the hypoxic environment of solid tumours.

Linalool, a plant-derived monoterpene alcohol, reverses doxorubicin resistance in human breast adenocarcinoma cells.

Essential oils from various aromatic plants have been reported to exert chemopreventive and/or antitumor effects. In addition, a number of studies have shown the ability of chemopreventive phytochemicals to increase the sensitivity of cancer cells to conventional anticancer drugs. The success of chemotherapeutic agents is often hindered by the development of drug resistance, with multidrug resistant (MDR) phenotypes reported in a number of tumors, generally involving reduced intracellular drug accumulation due to increased drug efflux by membrane transporters. In the present study, the effects of linalool (LIN), a monoterpene alcohol found in the essential oils from many aromatic plants, on the growth of two human breast adenocarcinoma cell lines, MCF7 WT and multidrug resistant MCF7 AdrR, were investigated, both as a single agent and in combination with doxorubicin (DOX). The results reported here show that LIN only moderately inhibits cell proliferation; interestingly, however, subtoxic concentrations of LIN potentiate DOX-induced cytotoxicity and pro-apoptotic effects in both cell lines. A significant synergism can be observed in MCF7 AdrR cells, which may be due, at least in part, to the ability of LIN to increase DOX accumulation and to induce a decrease in Bcl-xL levels. In summary, the results of the present study suggest that LIN may improve the therapeutic index of anthracyclines in the management of breast cancer, especially in MDR tumors.

Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line.

Metastatic breast cancer is an incurable disease, often characterized by poor response to standard chemotherapy, which is mainly based on anthracyclines and taxanes. Thus, increasing tumor cell sensitivity to these agents is an attractive goal towards improving the clinical management of this disease. The present study investigates the effects of signal transducer and activator of transcription 3 (Stat3) inhibition on the response of the highly metastatic MDA-MB-231 human breast adenocarcinoma cell line to doxorubicin (DOX). Stat3 is a transcription factor often constitutively activated in breast tumors and cancer cell lines, and is thought to contribute to malignant transformation and progression by transactivation of a host of target genes involved in cell proliferation and survival, angiogenesis and invasiveness. Our results indicate that (a) untreated MDA-MB-231 cells express higher baseline levels of (activated) pTyr(705)Stat3, that are further upregulated following exposure to DOX, than the non-metastatic MCF-7 cell line; (b) inhibiting the Stat3 signaling pathway, by exposure to the tyrphostin AG490 (an inhibitor of the upstream activating Janus kinases), by transfection with a dominant-negative form of Stat3 or by treatment with satraplatin (a tetravalent platinum derivative that inhibits Stat3 activation), increases breast cancer cell response to the proapoptotic effect of DOX (to different extents). In addition, the latter two approaches have been shown to interfere with expression of one or more antiapoptotic proteins. Overall, these observations suggest that suppression of Stat3 signaling may provide a potential therapeutic approach to overcoming DOX resistance in metastatic breast cancer cells.