Evaluation of the in vitro and in vivo antineoplastic effects ofParthenolide on MDA-MB231 breast cancer cells

Risultato della ricerca: Other

Abstract

Triple-negative breast cancer refers to an aggressive subtype of breast cancer in which thetumor cells lack receptors for estrogen, progesterone and the HER2 protein on their surfaces.This type of breast cancer does not respond to treatments such as hormone therapy, like tamoxifen and aromatase inhibitors, or drugs that target HER2, like Herceptin. It is important, therefore, the identification of new selective drugs for the treatment of these tumors.Parthenolide (PN), a sesquiterpene lactone extracted from the medical plant Tanacetum parthenium,exerts anticancer activity on several tumor cell lines in culture, acting through diversemolecular mechanisms. Our previous studies have shown that the PN exerts strong cytotoxiceffects on MG63 osteosarcoma and SK-Mel28 melanoma cells, through a caspase-independentmechanism which is associated with production of oxidative stress.Recently, we have undertaken a study in order to investigate the antineoplastic activity of PN onMDA-MB231 cells, a triple-negative breast cancer cell line. Our results demonstrated that thiscompound reduced the viability of MDA-MB231 cells in a dose- and time- dependent manner.This effect was not prevented by the addition of z-VAD-fmk, a general inhibitor of caspase, thussuggesting a caspase-independent cell death. Time-course experiments provided evidence thatthe cytotoxic effect of PN occurs in two different phases. In the first phase of treatment (8h) cellsresulted positive to monodansylcadaverine (MDC), a fluorochrome that binds to autophagic vacuoles.Prolonging the treatment (16h) MDC-positive cells lowered, and an increase of PI-positivepopulation was found, suggesting the appearance of necrotic events. The study of the modeof PN action provided evidence that treatment with parthenolide induces ROS generation, activationof JNK and inhibition of NF-kB activity. All these effects were prevented by the additionof NAC, thus suggesting the involvement of oxidative stress.The antineoplastic activity of PN has been also assayed in vivo employing diamminoparthenolide(DMAPT), a soluble analogue of PN. Nude mice bearing breast carcinoma MDA-MB231xenografts were treated daily with DMAPT (50 mg/Kg). It was observed that DMAPT increasedsurvival of MDA-MB231 xenograft-bearing nude mice as well as reduced MDA-MB231xenografts tumor growth. Moreover, immunohistochemical studies showed that DMAPT was able to decrease the expression of MMP-2, MMP-9 and VEGF, all factors involved in metastaticevents.These data suggest a possible use of parthenolide for the treatment of triple negative breastcancers.
Lingua originaleEnglish
Pagine58-
Numero di pagine1
Stato di pubblicazionePublished - 2012

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