Abstract
Triple-negative breast cancers (TNBCs) are clinically aggressive forms associated with a poor prognosis. We evaluated the cytotoxic effect exerted on triple-negative MDA-MB231 breast cancer cells both by parthenolide and its soluble analogue dimethylamino parthenolide (DMAPT) and explored the underlying molecular mechanism. The drugs induced a dose- and time-dependent decrement in cell viability, which was not prevented by the caspase inhibitor z-VAD-fmk. In particular in the first hours of treatment (1–3 h), parthenolide and DMAPT strongly stimulated reactive oxygen species (ROS) generation. The drugs induced production of superoxide anion by activating NADPH oxidase. ROS generation caused depletion of thiol groups and glutathione, activation of c-Jun N-terminal kinase (JNK) and downregulation of nuclear factor kB (NF-kB). During this first phase, parthenolide and DMAPT also stimulated autophagic process, as suggested by the enhanced expression of beclin-1, the conversion of microtubule-associated protein light chain 3-I (LC3-I) to LC3-II and the increase in the number of cells positive to monodansylcadaverine. Finally, the drugs increased RIP-1 expression. This effect was accompanied by a decrement of pro-caspase 8, while its cleaved form was not detected and the expression of c-FLIPS markedly increased. Prolonging the treatment (5–20 h) ROS generation favoured dissipation of mitochondrial membrane potential and the appearance of necrotic events, as suggested by the increased number of cells positive to propidium iodide staining. The administration of DMAPT in nude mice bearing xenografts of MDA-MB231 cells resulted in a significant inhibition of tumour growth, an increment of animal survival and a marked reduction of the lung area invaded by metastasis. Immunohistochemistry data revealed that treatment with DMAPT reduced the levels of NF-kB, metalloproteinase-2 and -9 and vascular endothelial growth factor, while induced upregulation of phosphorylated JNK. Taken together, our data suggest a possible use of parthenolide for the treatment of TNBCs.
Highlights
Parthenolide, a sesquiterpene lactone found in Tanacetum parthenium, known for its anti-inflammatory activity,[10] is considered as a novel anti-tumour agent
To ascertain the cause of the inhibitory effect and to differentiate apoptotic and necrotic cells, the cells were stained with Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) and analysed by flow cytometry at 8 and 16 h of treatment with 25 mM parthenolide (Figure 1d) or dimethylamino analogue of parthenolide (DMAPT) (Supplementary Figure S2A)
This paper investigates about the molecular mechanisms by which parthenolide and its soluble analogue DMAPT reduced in vitro viability of MDA-MB231 cells, which are hormoneinsensitive human breast cancer cells
Summary
Parthenolide, a sesquiterpene lactone found in Tanacetum parthenium, known for its anti-inflammatory activity,[10] is considered as a novel anti-tumour agent. We showed that parthenolide exerts cytotoxicity on osteosarcoma and melanoma cells[19] through a caspaseindependent mechanism correlated with ROS generation. Despite the high efficacy of parthenolide in vitro, its pharmacological use is difficult owing to the scarce solubility.[20] Recently, a dimethylamino analogue of parthenolide (DMAPT) has been generated, which improves solubility and bioavailability and exhibits an acceptable toxicological profile in animal studies.[21,22] DMAPT eradicates primary leukaemia stem cells[21] and suppresses in vivo the growth of prostate,[22] lung and bladder cancers,[23] by targeting NF-kB and generating ROS. We demonstrate that DMAPT significantly decreases tumour growth in mice bearing xenografts of MDAMB231 cells and enhances survival of treated mice. Immunohistochemical studies show that DMAPT decreases in vivo the levels of metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF), all factors involved in metastatic events
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