Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production.

The antimalarial agent artesunate (ART) activates programmed cell death (PCD) in cancer cells in a manner dependent on the presence of iron and the generation of reactive oxygen species. In malaria parasites, ART cytotoxicity originates from interactions with heme-derived iron within the food vacuole. The analogous digestive compartment of mammalian cells, the lysosome, similarly contains high levels of redox-active iron and in response to specific stimuli can initiate mitochondrial apoptosis. We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization. Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. ART killing did not involve activation of the BH3-only protein, Bid, yet ART enhanced TNF-mediated Bid cleavage. We additionally demonstrated the lysosomal PCD pathway in T47D and MDA-MB-231 breast cancer cells. Importantly, non-tumorigenic MCF-10A cells resisted ART-induced PCD. Together, our data suggest that ART triggers PCD via engagement of distinct, interconnected PCD pathways, with hierarchical signaling from lysosomes to mitochondria, suggesting a potential clinical use of ART for targeting lysosomes in cancer treatment.

Bilateral synchronous submandibular lumps in a patient with gastric carcinoma.

This case report deals with a patient who was readmitted with a bilateral submandibular swelling after having received primary surgery due to gastric adenocarcinoma 6 months before. After bilateral submandibulectomy both glands were diagnosed histopathologically as metastasis of adenocarcinoma. This is the rare case of a submandibular gland metastasis and the first case of a bilateral synchronous submandibular gland metastasis from gastric carcinoma.

The in situ expression of interleukin-8 in the normal human kidney and in different morphological forms of glomerulonephritis.

BACKGROUND: Interleukin-8 (IL-8) is considered a deleterious chemokine involved in renal injury in glomerulonephritis (GN). IL-8 may be released as a 77-amino acid (AA) peptide or 72-AA protein. METHODS: We evaluated gene and protein expression of IL-8 in 53 renal biopsy specimens from patients with GN and 9 control kidneys. Nonradioactive in situ hybridization and reverse-transcriptase polymerase chain reaction (RT-PCR) were applied to detect IL-8 messenger RNA (mRNA). In immunohistochemistry, a double-staining technique with the use of antibodies against the 77-AA and 72-AA forms of IL-8, as well as glomerular cell antigens, was used. RESULTS: By in situ hybridization, IL-8 mRNA was detected in normal glomerular, tubular, and some interstitial cells. The RT-PCR study showed that IL-8 mRNA expression in control kidneys significantly exceeds that in specimens with GN (0.89 +/- 0.82 versus 0.21 +/- 0.20; P < 0.003). In control kidneys, major sources of 77-AA IL-8 were podocytes and endothelial cells of interstitial vessels, whereas tubular epithelial cells expressed minute amounts of 72-AA IL-8. In GN specimens, podocyte expression of 72-AA IL-8 varied notably, with the greatest level found in minimal change disease and the lowest level found in acute endocapillary GN. Conversely, increased glomerular expression of the 72-AA form of IL-8 was a general feature of GN, with its level significantly exceeding that of the 77-AA form in acute endocapillary GN (P < 0.01). CONCLUSION: Our results suggest that intrinsic glomerular cell production of IL-8, in particular the 77-AA form, may be relevant for preservation of the glomerular architecture.