An Active Compound from the Pyrazine Family Induces Apoptosis by Targeting the Bax/Bcl2 and Survivin Expression in Chronic Myeloid Leukemia K562 Cells.

BACKGROUND: It has been established that pyrazine derivatives, which have widespread bioactivities, can effectively treat cancer. OBJECTIVES: In this study, we investigated the effects of 2-methoxy-5-(oxiran-2-ylmethyl) phenyl pyrazine-2- carboxylate (2-mOPP), a new pyrazine derivative, on proliferation, viability, and apoptosis induction in human leukemia K562 cells. METHODS: For this purpose, the K562 cells were treated with various concentrations (20-120 µM) of the 2-mOPP for 24-72 hours. Cell viability was determined by MTT growth inhibition assay. Apoptotic activity of 2-mOPP was investigated morphologically by Hoechst staining, cell surface expression assay of phosphatidylserine by Annexin-V/PI technique, as well as DNA fragmentation assay. The effect of 2-mOPP on the K562 cell cycle was studied by flow cytometry. To determine the impact of 2-mOPP on the expression of intrinsic apoptosis-related genes, Bcl2 (anti-apoptotic), Bax (pro-apoptotic), and Survivin genes expression levels were evaluated before and after treatment with 2-mOPP through Real-Time PCR analysis. RESULTS: The results revealed that 2-mOPP inhibited viability with IC50 of 25µM in 72 h. Morphological changes assessment by fluorescence microscopy, Annexin V/PI double staining by flow cytometry, and DNA ladders formation upon cell treatment with the 2-mOPP showed that this compound induces apoptosis at IC50 value. Cell cycle arrest was observed in the G0/G1 phase, and the sub-G1 cell population (the sign of apoptosis) increased in a time-dependent manner. Low expression levels of Bcl2 and Survivin in K562 cells were observed 24-72 h after treatment. Along with the down-regulation of Survivin and Bcl2, the expression of Bax was increased after treatment with 2-mOPP. CONCLUSION: These findings demonstrate that the new pyrazine derivative plays a crucial role in blocking the proliferation of the leukemic cells by inducing cell cycle arrest and apoptosis.

Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs.

Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.

Down-regulation of Survivin and Bcl-2 concomitant with the activation of caspase-3 as a mechanism of apoptotic death in KG1a and K562 cells upon exposure to a derivative from ciprofloxacin family.

Ciprofloxacin derivatives belong to a family of antibiotics called fluoroquinolones. Recently, these compounds have been recommended for the treatment of cancer. In the present study, we assessed the cytotoxicity of several new synthetic ciprofloxacin derivatives and the apoptosis-inducing activity of the most efficient derivative in two human myeloid leukemia K562 and KG1-a cell lines. Among the prepared ciprofloxacin derivatives, 1-cyclopropyl-7-(4-(2-((3,7-dimethyloct-6-en-1-yl)oxy)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (4-DMOCP) was more active compound with IC50 of 19.56 and 22.13 µM for K562 and KG1-a, respectively. Apoptotic activity of the 4-DMOCP was examined morphologically through Hoechst 33258 staining, Annexin V/PI double staining, and caspase-3 activity assays. Changes in the expression level of some apoptosis-related genes and protein, including Bcl-2, Bax, Survivin, p53, Caspase-8 and Caspase-9 were evaluated by the real-time quantitative PCR (qRT PCR) and western blotting. The qRT PCR analysis showed that 4-DMOCP induces apoptosis in both cell lines via the down-regulation of Survivin and Bcl2, up-regulation of caspase-8 and -9, as well as a time-dependent increase in the Bax/Bcl2 transcripts. The mRNA level of p53 was also increased in both cell lines. In addition, western blot analysis revealed that treatment with the compound, down-regulated the protein expression levels of Bcl2 and Survivin and up-regulated the protein level of Bax in both cell lines. These findings suggest that these new compounds can be good candidates for the treatment of acute and chronic myeloid leukemia.

Epidemiology of upper gastrointestinal cancers in Iran: a sub site analysis of 761 cases.

AIM: To define the sub site distribution of upper gastrointestinal cancers in three provinces of Iran. METHODS: The study was carried out in three provinces in Iran: Ardabil, Golestan, and Tehran. In Arbabil and Golestan, the data was collected from the sole referral center for gastrointestinal cancers and the local cancer registry. For Tehran province, data from two major private hospitals were used. All gastric and esophageal cancer patients diagnosed during the period from September 2000 and April 2002 were included in the study. RESULTS: A total of 761 patients with upper gastrointestinal cancers were identified, 314 from Ardabil, 261 from Golestan, and 186 from Tehran. In Tehran, the relative rate of cancer increased from the upper esophagus to the distal stomach. In Golestan, the reverse pattern was observed. In Ardabil, the mid portion (distal esophagus and proximal stomach) was involved most frequently. CONCLUSION: There were considerable variations in the sub site of upper gastrointestinal cancers in the three provinces studied. We cannot provide any explanation for this variation. Further research aimed at explaining the discrepancies in sub site distribution of upper gastrointestinal cancers may help identify important risk factors.