Expression of VDAC (Voltage-Dependent Anion Channel) isoforms in hematological cancers

Voltage-Dependent Anion Channels (VDACs), also known as mitochondrial porins, are proteins located in the mitochondrial outer membrane (OMM). In humans there are three VDAC isoforms namely VDAC1, VDAC2 and VDAC3, encoded by three different genes with high level of homology. VDACs form pores through OMM and are involved in mitochondrial metabolic and energetic functions and in apoptotic cell death [1]. VDACs exchange metabolites between cytoplasm and mitochondria and serve as anchor point for mitochondria-interacting proteins [2-3]; in particular hexokinase II (HKII) binds to VDAC in cancer cells and provides both metabolic advantage and anti-apoptotic activity [4]. With the aim to evaluate if VDACs are useful prognostic markers for hematological cancers, we analyzed, by Real time PCR, expression levels of VDACs genes in bone marrow cells derived from patients with Acute Myeloid Leukemia (AML), Multiple Myeloma (MM) at the outset of the disease and in bone marrow cells derived from healthy subjects. The results found show that patients with VDAC2 and/or VDAC1 isoforms up-regulated had poor prognosis. Moreover, VDAC3 was down regulated in all patients with poor prognosis and HKII was up-regulated in almost all samples. Although these results have been observed on a limited number of samples, they suggest that VDAC1 and VDAC2 have anti-apoptotic activity in hematological cancers and could explain cancer cells survival in patients with poor prognosis. If these results will be confirmed on a larger number of patients, expression level of VDACs could be used as prognostic marker of hematological cancers. [1] V. Shoshan-Barmatz, et al (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol. Aspects Med. 31, 227-85. [2] A. Messina, et al (2012) VDAC isoforms from mammals. Biochim Biophys Acta, 1818, 1466-1476. [3] S. Reina, et al. (2010) Swapping of the N-terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti-aging features to the cell. FEBS Letters 584, 2837-44

Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia

Objective: Azacitidine is the standard of care for higher-risk myelodysplastic syndromes (MDS). We evaluated factors affecting the outcome of azacitidine treatment in 196 'real-world' patients, retrospectively collected by two Italian cooperative groups. Methods: The study included 184 MDS and 12 low blast count acute myeloid leukemia (AML). Azacitidine was administered at the standard dose of 75 mg/m2/d for 7 d (SD) in 163 patients and 100 mg/d for 5-7 d in 33 patients. Results: After a median of 4.5 azacitidine cycles (range 7-15 cycles), 182 patients were evaluable for response. Nineteen percent achieved complete remission (CR), 17% partial remission (PR), and 21% hematological improvement (HI). The disease was stable or progressive in 29% and 14% of patients, respectively. The probability of response was significantly higher in patients who received the 75 mg/m2/7 d compared with 100 mg through 5-7 d dose (CR/PR/HI: 63 vs. 29%, P = 0.0005). Median overall survival was 17.1 months. Low MDS-CI and achievement of CR/PR/HI were significant predictors of survival in the multivariable analysis. Conclusions: Our data show that maximal azacitidine efficacy is associated with the standard dose and with prolonged treatment, beyond 4-6 cycles, with the goal of also improving the 'quality' of response. Lower MDS-CI and IPSS-R scores, hematologic response and disease stability, are associated with longer survival. The risk of febrile events is highest during the first treatment cycles and is associated with active disease

Azacitidine for the treatment of lower risk myelodysplastic syndromes: A retrospective study of 74 patients enrolled in an Italian named patient program

BACKGROUND: Azacitidine induces responses and prolongs overall survival compared with conventional care regimens in patients who have high-risk myelodysplastic syndromes (MDS). However, limited data are available concerning the efficacy and safety of azacitidine in patients who have lower risk MDS. METHODS: The authors retrospectively evaluated 74 patients with International Prognostic Scoring System low-risk or intermediate 1-risk MDS, who received azacitidine on a national named patient program. At baseline, 84% of patients were transfusion-dependent, 57% had received erythropoietin, and 51% were aged >70 years. Azacitidine was administered subcutaneously for 5 days (n = 29 patients), 7 days (n = 43 patients), or 10 days (n = 2 patients) every month at a dose of 75 mg/m2 daily (n = 45 patients) or at a fixed dose of 100 mg daily (n = 29 patients) and for a median of 7 cycles (range, 1-30 cycles). RESULTS: According to the 2006 International Working Group criteria, overall response rate (ORR) was 45.9%, including complete responses (10.8%), partial responses (9.5%), hematologic improvements (20.3%), and bone marrow complete responses (5.4%). The ORR was 51.6% in 64 patients who completed ≥4 cycles of treatment. The median duration of response was 6 months (range, 1-30 months). After a median follow-up of 15 months, 71% of patients remained alive. A survival benefit was observed in responders versus nonresponders (94% vs 54% of patients projected to be alive at 2.5 years, respectively; P < .0014). The most common grade 3 or 4 adverse events were myelosuppression (21.6%) and infection (6.8%). CONCLUSIONS: The current results indicated that azacitidine may be a feasible and effective treatment for patients with lower risk MDS. © 2010 American Cancer Society