The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections

The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections

The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections.</p

Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole

Abstract: Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC50 0.36–13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC50 12.2–26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ 0 cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, Mar. Drugs 2012, 10 90