ß-lactam Structured, 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one: Selectively Targets Cancerous B Lymphocyte Mitochondria.

BACKGROUND: ß lactam-structured Cox-2 inhibitors, possesses anti-proliferative and anti-inflammatory effects. OBJECTIVE: In this research, the actions of a synthetic ß lactam-structured Cox-2 inhibitor with 4-(4- (Methylsulfonyl) phenyl)-1-pentyl-3-phenoxyazetidin-2-one on cellular viability of cancerous lymphoblast obtained from patients with acute lymphocytic leukemia (ALL) and normal lymphocytes obtained from healthy donors were compared. METHODS: % the cell viability of cancerouslymphoblasts and normal lymphocytes treated with ß lactam derivatives were assayed with MTT test. Early apoptosis and necrosis were detected by double staining of annexin V/ propidium iodide and activity of caspase 3 as the final mediator in apoptotic mode of cell death was evaluated by colorimetric assay. RESULTS: Our results showed that ß lactam derivatives inhibited the proliferation of cancerous lymphoblast but not normal lymphocytes in a concentration-dependent mode by inducing apoptosis. Treatment with ß lactam derivatives resulted in a rapid loss of mitochondrial trans-membrane potential and induction of reactive oxygen species (ROS) formation, and cytochrome c release in cytosol of mitochondria resulted in activation of procaspase-9 and formation of active apoptosome. CONCLUSION: These findings suggest that 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one as a ß lactam could induce ROS-mediated death signaling throughmitochondrial pathway that results in apoptosis in only cancerous lymphoblast cells. The stimulationof apoptosis by ß lactams may provide a pivotal mechanismfor their anticancer effect in acute lymphocytic leukemia cells.

Chrysin as an Anti-Cancer Agent Exerts Selective Toxicity by Directly Inhibiting Mitochondrial Complex II and V in CLL B-lymphocytes.

We investigated the effect of chrysin on isolated normal and chronic lymphocytic leukemia (CLL) B-lymphocytes and their isolated mitochondria. We report that a selective and significant increase in cytotoxicity, intracellular reactive oxygen species, mitochondrial membrane potential collapse, ADP/ATP ratio, caspase 3 activation and finally apoptosis in chrysin-treated CLL B- lymphocytes. Also we determined that chrysin selectively inhibits complex II and ATPases in cancerous mitochondria. In this study we proved that the ability of chrysin to promote apoptosis in CLL B-lymphocytes performed by selectively targeting of mitochondria. Our findings may provide a potential therapeutic approach for using chrysin to target mitochondria in CLL B-lymphocytes.

Selective Anticancer Activity of Acacetin Against Chronic Lymphocytic Leukemia Using Both In Vivo and In Vitro Methods: Key Role of Oxidative Stress and Cancerous Mitochondria.

The present study investigates the in vitro and in vivo effect of acacetin (4'-methoxy-5,7-dihydroxyflavone) on chronic lymphocytic leukemia (CLL) B-lymphocytes and mitochondria. CLL B-lymphocytes and healthy B-lymphocytes were obtained from CLL patients and healthy donors, respectively. Mitochondria were isolated from B-lymphocytes of both groups. Xenografts in severe combined immune deficient mice were used to examine the toxicity and anti CLL activity of acacetin. We evaluated and compared the mechanism of action of acacetin on CLL and healthy B-lymphocytes and their mitochondria. We have found that acacetin (10 µM) can selectively induce apoptosis on CLL B-lymphocyte (25% at 24 h) by directly targeting mitochondria, through increased reactive oxygen species (ROS) formation, MMP collapse, MPT, release of cytochrome c, caspase 3 activation, and finally apoptosis, while sparing normal healthy B-lymphocytes unaffected at similar concentrations. Besides, oral administration of acacetin showed a potent in vivo anticancer activity in CLL xenograft mouse models. Our in vivo findings indicate that acacetin accumulates and kills CLL B-lymphocyte in a rather selective way through targeting cancerous mitochondria and ROS formation, which ends in CLL therapy. Finally, we can recommend acacetin as a promising compound for further drug development assays for the CLL treatment.

Ellagic acid, a polyphenolic compound, selectively induces ROS-mediated apoptosis in cancerous B-lymphocytes of CLL patients by directly targeting mitochondria.

To investigate the effects ofellagic acid (EA) on the cytotoxicity, B-lymphocytes isolated from CLL patients and healthy individuals. Flow cytometric assay was used to measure the percentage of apoptosis versus necrosis, intracellular active oxygen radicals (ROS), mitochondrial membrane potential (MMP) and the caspase-3 activity and then mitochondria were isolated from both groups B-lymphocytes and parameters of mitochondrial toxicity was investigated. Based on our results EA decreased the percentage of viable cells and induced apoptosis. EA increased ROS formation, mitochondria swelling, MMP decrease and cytochrome c release in mitochondria isolated from CLL BUT NOT healthy B-lymphocytes while pre-treatment with cyclosporine A and Butylated hydroxyl toluene (BHT) prevented these effects. Our results suggest that EA can act as an anti cancer candidate by directly and selectively targeting mitochondria could induce apoptosis through mitochondria pathway with increasing ROS production which finally ends in cytochrome c release, caspase 3 activation and apoptosis in cancerous B-lymphocytes isolated from CLL patients.