Zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, demonstrates potent antitumor effects but is unable to potentiate antitumor effects of chemotherapeutics in mice

Nowis, Dominika; Bugajski, Marek; Winiarska, Magdalena; Bil, Jacek; Szokalska, Angelika; Salwa, Pawel; Issat, Tadeusz; Waś, Halina; Józkowicz, Alicja; Dulak, Józef; Stokłosa, Tomasz; Gołąb, Jakub

doi:10.1186/1471-2407-8-197

Cited by 63 publications

(54 citation statements)

References 34 publications

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“…A potential limitation of the present study is the heavy reliance on pharmacological agents to dissect signaling pathways [e.g., compound C, STO-609, and Zn(II)PPIX], leaving open the possibility for off-target effects. However, at the concentrations used, the compounds [STO-609 (5 mM), compound C (10 mM), and Zn(II)PPIX (5 mM)] are likely to have acted relatively specifically (Zhou et al, 2007;Nowis et al, 2008;Reihill et al, 2011;Guo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Tian

Xia

et al. 2014

J Pharmacol Exp Ther

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This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKb (Ca 2+ /calmodulin-dependent protein kinase kinase-b) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKb/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKb or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-b, which in turn activates the AMPKNrf-2-HO-1 pathway for enhanced endothelial function.

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Section: Discussionmentioning

confidence: 99%

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Tian

Xia

et al. 2014

J Pharmacol Exp Ther

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“…20 Moreover, as expected, CoPP IX also induced HO-1 protein expression ( Figure 1A) and HO-1 activity ( Figure 1B) in a time-dependent manner, with a maximal response within 16 to 24 hours in HTSMCs. ZnPP IX, an inhibitor of HO-1 activity, 21 blocked CoPP IX-induced HO-1 activity ( Figure 1B). To further determine the role of Nrf2 in CoPP IX-mediated HO-1 induction, cells were transfected with Nrf2 siRNA.…”

Section: Copp IX Induces Ho-1 Expression and Activity Through Nrf2 Inmentioning

confidence: 99%

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

Lee

Luo

Lee

et al. 2009

The American Journal of Pathology

157

151

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Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-␣-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-␣-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47 phox translocation, and nuclear factor-B activation. HO-1 overexpression also attenuated TNF-␣-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47 phox complex. These results suggest that HO-1 functions as a suppressor of TNF-␣ signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-B activation in both cultured human tracheal smooth muscle cells and the airways of mice.

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“…The up-regulation of HO-1 has also been identified in several disease states including many cancers, such as prostate cancer (Maines and Abrahamsson, 1996) and pancreatic cancer (Berberat et al, 2005). Furthermore, HO-1 can be up-regulated in response to anticancer treatments (Berberat et al, 2005;Nowis et al, 2006), which has been interpreted to indicate that HO-1 plays an important role in the survival and proliferation of tumors and its inhibition may lead to decreased tumor survival, as has been demonstrated previously (Fang et al, 2004;Hirai et al, 2007;Nowis et al, 2008).…”

Section: Introductionmentioning

confidence: 71%

The Effects of Azole-Based Heme Oxygenase Inhibitors on Rat Cytochromes P450 2E1 and 3A1/2 and Human Cytochromes P450 3A4 and 2D6

Hum¹,

McLaughlin²,

Roman³

et al. 2010

J Pharmacol Exp Ther

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Heme oxygenases (HOs) catalyze the degradation of heme to biliverdin, carbon monoxide (CO), and free iron. The two major isoforms, HO-1 (inducible) and HO-2 (constitutive), are involved in a variety of physiological functions, including inflammation, apoptosis, neuromodulation, and vascular regulation. Major tools used in exploring these actions have been metalloporphyrin analogs of heme that inhibit the HOs. However, these tools are limited by their lack of selectivity; they affect other hemedependent enzymes, such as cytochromes P450 (P450s), soluble guanylyl cyclase (sGC), and nitric-oxide synthase (NOS). Our laboratory has successfully synthesized a number of nonporphyrin azole-based HO inhibitors (QC-xx) that had little or no effect on sGC and NOS activity. However, their effects on various P450 isoforms have yet to be fully elucidated. To determine the effects of the QC-xx inhibitors on P450 enzyme activity, microsomal preparations of two rat P450 isoforms (2E1 and 3A1/3A2) and two human P450 supersome isoforms (3A4 and 2D6) were incubated with varying concentrations of HO inhibitor, and the activity was determined by spectrophotometric or fluorometric analysis. Results indicated that some QC compounds demonstrated little to no inhibition of the P450s, whereas others did inhibit these P450 isoforms. Four structural regions of QC-xx were analyzed, leading to the identification of structures that confer a decreased effect on both rat and human P450 isoforms studied while maintaining an inhibitory effect on the HOs.

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Zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, demonstrates potent antitumor effects but is unable to potentiate antitumor effects of chemotherapeutics in mice

Cited by 63 publications

References 34 publications

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

The Effects of Azole-Based Heme Oxygenase Inhibitors on Rat Cytochromes P450 2E1 and 3A1/2 and Human Cytochromes P450 3A4 and 2D6

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