37 research outputs found
Evidence of ER stress and UPR activation in patients with Brody disease and Brody syndrome
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Bortezomib-induced muscle toxicity in multiple myeloma
No full textMultiple myeloma (MM) accounts for ~13% of all hematologic malignancies. Bortezomib treatment is effective in MM, but can be complicated with neurological side effects. We describe a patient with symptomaticMM who had a reversible metabolic myopathy associated with bortezomib administration and pathologically characterized by excessive storage of lipid droplets together with mitochondrial abnormalities. In a single-center prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, 7 developed muscular signs and/or symptoms. The myopathy was characterized by a proximal muscle weakness involving lower limbs and was an early complication. Complete resolution of muscle weakness occurred after treatment discontinuation. Conversely, none of the patients who received a treatment without bortezomib developed muscular symptoms. Experimental studies demonstrate that in primary human myoblasts bortezomib at low concentrations leads to excessive storage of lipid droplets together with structural mitochondrial abnormalities, recapitulating the pathologic findings observed in patient's muscle. Our data suggest that patients treated with bortezomib should be monitored for muscular signs and/or symptoms and muscle weakness should alert the clinician to the possibility of myopathy. Bortezomib-induced metabolic myopathy is a potentially reversible entity with important implications for management and treatment of patients with MM
Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response
No full textPhotodynamic 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.sponsorship: Grant support: Ministry of Science and Higher Education-Poland grants N40112331/2736, R0504303 (J. Golab), and N401324033 (D. Nowis); Medical University of Warsaw grants 1M19/N (M. Jakobisiak), 1M19/WB1/07 (M. Jakobisiak), 1M19/WB2/07 (D. Nowis), and 1M19/NM2/07 (P. Salwa); K.U.Leuven grant OT/06/49 (P. Agostinis); "Fonds voor Wetenschappelijk Onderzoek" (FWO)-Vlanderen grant G.0492.05 (P. Agostinis); U.S. NIH grant R01-CA/AI838801 (M.R. Hamblin and P. Mroz); and an institutional appropriation of the American Cancer Society grant IRG-84-002-22 (C. Wojcik). T. Issat is a recipient of the START stipend from the Foundation for Polish Science. (Ministry of Science and Higher Education-Poland|N40112331/2736, Ministry of Science and Higher Education-Poland|R0504303, Ministry of Science and Higher Education-Poland|N401324033, Medical University of Warsaw|1M19/N, Medical University of Warsaw|1M19/WB1/07, Medical University of Warsaw|1M19/WB2/07, Fonds voor Wetenschappelijk Onderzoek|G.0492.05, NIH|R01-CA/AI838801, American Cancer Society|IRG-84-002-22, Foundation for Polish Science.)status: Publishe
Co-delivery of indoleamine 2,3-dioxygenase prevents loss of expression of an antigenic transgene in dystrophic mouse muscles
No full textImmunogenic cell death, DAMPs and anticancer therapeutics: An emerging amalgamation
No full textImmunogenic profile of certain cancer cell death mechanisms has been transmuted by research published over a period of last few years and this change has been so drastic that a new (sub)class of apoptotic cancer cell death, redefined as ‘immunogenic apoptosis’ has started taking shape. In fact, it has been shown that this chemotherapeutic agent-specific immunogenic cancer cell death modality has the capabilities to induce ‘anticancer vaccine effect’, in vivo. These new trends have given an opportunity to combine tumour cell kill
and antitumour immunity within a single paradigm, a sort of ‘holy grail’ of anticancer therapeutics. At the molecular level, it has been shown that the immunological silhouette of these cell death pathways is defined by a set of molecules called ‘damage-associated molecular patterns (DAMPs)’. Various intracellular molecules like calreticulin (CRT), heat-shock proteins (HSPs), high-mobility group box-1 (HMGB1) protein,
have been shown to be DAMPs exposed/secreted in a stress agent/factor-and cell death-specific manner. These discoveries have motivated further research into discovery of new DAMPs, new pathways for their exposure/secretion, search for new agents capable of inducing immunogenic cell death and urge to solve currently present problems with this paradigm. We anticipate that this emerging amalgamation of DAMPs, immunogenic cell death and anticancer therapeutics may be the key towards squelching cancer-related mortalities, in near future
Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma
No full textBACKGROUND/AIMS: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit growth and to induce apoptosis in human hepatocellular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, which prompted us to test the efficacy of pravastatin in patients with advanced HCC. METHODS: We investigated prospectively a cohort of 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20-40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. RESULTS: During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5-26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3-13.7). CONCLUSION: Combined treatment of chemoembolization and pravastatin improves survival of patients with advanced HCC in comparison to patients receiving chemoembolization alone
Co-delivery of indoleamine 2,3-dioxygenase prevents loss of expression of an antigenic transgene in dystrophic mouse muscles.
No full textA significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy. This treatment prevented loss of expression of the transgene concomitant with significantly elevated expression of T-regulatory (Treg) markers in the IDO1-expressing muscles. Moreover, co-expression of IDO1 resulted in reduced serum levels of anti-β-gal antibodies. These data indicate that co-expression of genes encoding immunomodulatory enzymes controlling kynurenine pathways provide a viable strategy for preventing loss of transgenes targeted into dystrophic muscles with pre-existing inflammation
Peroxiredoxin-1 as a prognostic factor in patients with ovarian cancer
No full textIntroduction and objective. Peroxiredoxin-1 (PRDX-1) belongs to a family of antioxidant enzymes and has proved to be a versatile molecule regulating cell growth, differentiation and apoptosis. PRDX1-regulated signaling pathways play an important role in the progression and metastasis of human tumours, especially in breast, esophageal and lung cancers. The aim of the study was to evaluate the expression of PRDX-1 in ovarian cancer tissues, and to test the clinical value of PRDX-1 as a prognostic factor in this malignancy.
Materials and method. PRDX-1 expression was assessed by automated immunohistochemistry in tumours taken from 55 patients with ovarian cancer during primary surgery. Specimen were formalin-fixed and preserved in paraffin-embedded blocks. The results were correlated with clinicopathological data.
Results. A high expression of PRDX-1 was observed in 20% of cases, and was associated with worse compliance to chemotherapy protocol (P<0.002), worse response to chemotherapy (P<0.04), and higher levels of CA 125 after the 1st line treatment (P<0.004). PRDX-1 positive subjects had a significantly lower 5-year disease-free survival (9.1% vs. 42.6%, P<0.01) and a lower 5-year overall survival (9.1% vs. 56.7%; P<0.002). Multivariate analysis showed that a high expression of PRDX-1 is an independent prognostic factor of poor, overall survival (P<0.002) and a disease-free survival (P<0.01).
Conclusion. Results of the study show that PRDX-1 expression in tumour tissues can be another biomarker of prognosis in patients with ovarian cancer
Co-delivery of indoleamine 2,3-dioxygenase prevents loss of expression of an antigenic transgene in dystrophic mouse muscles
No full textSarcolemmal Ca2+-ATPase ability to transport Ca2+ gradually diminishes after myocardial infarction in the rat.
No full textAIMS: Plasmalemmal Ca(2+)-ATPase (PMCA) is involved in Ca(2+) handling and the regulation of intracellular signalling pathways in the heart. However, there is no information on its functioning in heart hypertrophy and failure. We aimed to investigate the Ca(2+)-transporting ability of PMCA, Na(+)/Ca(2+) exchanger (NCX), and sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), as well as the amplitude of Ca(2+) transients and cell shortening in myocytes isolated from rat hearts at various time intervals after myocardial infarction (MI). METHODS AND RESULTS: The rate of Ca(2+) transport by PMCA, NCX, and SERCA2a was estimated from the rate constants of decay of electrically and caffeine-evoked Ca(2+) transients in left ventricular myocytes isolated 1 week, 1 month, and 3 months after MI. One week, 1 month, and 3 months after MI, the transporting function of PMCA decreased by 27, 41, and 67%, respectively, compared with that in time-matched sham animals. This was accompanied by increased amplitude of Ca(2+) transients, cell shortening, and SR Ca(2+) content. Carboxyeosin, a blocker of PMCA, increased the amplitude of shortening in cells extracted from control hearts. This effect was absent 1 and 3 months after MI. PMCA1, 2, and 4 mRNAs were unchanged in the ventricular muscle 3 months after MI when compared with time-matched sham animals. The transporting function of NCX was increased by 65% only 3 months after MI, whereas that of SERCA2a was decreased by approximately 18% at all three time points after MI. CONCLUSION: The ability of PMCA to transport Ca(2+) progressively decreases over 3 months after MI. This decrease may contribute to the increase in amplitude of Ca(2+) transients and myocyte shortening
