Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. [Cancer Res 2009;69(10):4235-43]

The aim of the present study was to examine the potential antitumor activity of lovastatin and other statins together with pamidronate, a second generation bisphosphonate (BP), against tumor cell lines. Cytostatic/cytotoxic effects were measured using crystal violet assay. Regulation of the cell cycle and induction of apoptosis were evaluated using flow cytometry and Western blotting, migration of tumor cells was measured in a scratch wound assay and their invasiveness was measured with a Matrigel-invasion assay. Antitumor effects of the combination treatment were evaluated in a murine PANC 02 pancreatic adenocarcinoma model. Combination of pamidronate and lovastatin produced potentiated cytostatic/ cytotoxic effects against breast and pancreatic cancer cell lines. The combination was also effective in inhibition of tumor cell adhesion to collagen IV and fibronectin and interfered with migration and invasiveness of tumor cells. Neither pamidronate nor lovastatin alone affected tumor growth in mice but the combination treatment resulted in retardation of tumor growth and prolongation of mouse survival. The combination of statins and pamidronate, a second generation bisphosphonate, demonstrates promising antitumor effects at doses readily achievable in patients. This combination holds promise for future clinical studies.

SummaryBackground:Despite the fact that joint tuberculosis is one of the most common forms of extrapulmonary tuberculosis, it is a disease entity that is very rare in Poland (less than 100 cases a year in the last 10 years). The symptoms are non-specific, and thus the disease is rarely taken into account in preliminary differential diagnosis.Case Report:A 68-year-old female patient was admitted to the Internal Diseases Clinic due to oedema and pain of the right shoulder joint. The pain has been increasing for about 8 months. Physical examination revealed increased circumference and elevated temperature of the right shoulder joint. Limb function was retained. The full range of radiological and laboratory diagnostic examinations was performed, including the biopsy of the affected tissue which revealed the presence of Mycobacterium tuberculosis in the bacterial culture. Clinical improvement was obtained after introduction of TB drugs.Conclusions:Radiological diagnostic methods (X-ray, CT scans, MRI scans) provide high precision monitoring of articular lesions. However, the decisive diagnosis requires additional laboratory tests as well as histopathological and bacteriological assays.

The frequency of coronary heart disease and myocardial infarction in 500 persons with rheumatoidearthritis (116 men and 384 women) receiving salicylates during long period time were examined. Coronary heart disease in 2 cases (1 man and 1 woman) and myocardial infarction in 1 man were found.On the basis of the age and duration observations the authors discovered that the coefficient morbidity was statistically significant lower than in the same population but without rheumatoid arthritis. The coronary risk factors as hypertenia arterialis, hyper-cholestrolemia and diabetes was less frequent than in normal population too. The cigarettes smoking and obesity were found equally frequent.The authors suggested that long term treatment with acetylsalicylic acid effects inhibition adhesion of platelets and in this way protects before arterial thrombosis and may be artherosclerosis.

Supplementary Table 1, Methods and Materials, Figure Legends 1-6 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response