Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (Rs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and R ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/Rs) 14 containing the chemical features needed for HO-1 inhibition and R modulation. Herein, we report for the first time that targeting simultaneously HO-1 and R proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/Rs hybrids to develop novel potential anticancer agents.

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Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

Journal of Translational Medicine ◽

10.1186/1479-5876-12-89 ◽

2014 ◽

Vol 12 (1) ◽

pp. 89 ◽

Cited By ~ 14

Author(s):

Claudia Kusmic ◽

Cristina Barsanti ◽

Marco Matteucci ◽

Nicoletta Vesentini ◽

Gualtiero Pelosi ◽

...

Keyword(s):

Infarct Size ◽

Experimental Evidence ◽

Heme Oxygenase ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Heme Oxygenase 1 ◽

Proof Of Concept ◽

Evidence And Proof

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Motexafin Gadolinium and Other Metallotexaphyrins Upregulate Heme Oxygenase-1.

Blood ◽

10.1182/blood.v106.11.4468.4468 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4468-4468

Author(s):

Mint Sirisawad ◽

Jun Chen ◽

Jason Ramos ◽

Richard A. Miller ◽

Louie Naumovski

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Chemical Structure ◽

Heme Oxygenase 1 ◽

Oxygen Species ◽

Redox Stress ◽

Motexafin Gadolinium ◽

Protein Thiols ◽

Tin Protoporphyrin ◽

First Time

Abstract Heme oxygenase-1 (HO-1) is an inducible enzyme that is upregulated by heme and acts to degrade heme into bilirubin, carbon monoxide and iron. HO-1 is known to be upregulated in response to oxidative stress and has anti-apoptotic properties. Motexafin gadolinium (MGd, Xcytrin®) is a tumor-selective redox mediator that produces oxidative stress in cancer cells by reacting with various reducing metabolites and protein thiols to generate reactive oxygen species. Also, MGd is an expanded porphyrin that has a chemical structure which resembles heme. Since redox stress and heme upregulate HO-1 expression, we hypothesized that MGd would produce similar effects. We treated 8 hematopoietic tumor-derived cell lines with MGd and found that 2 of them (Ramos and HF-1) upregulated HO-1 protein. In Ramos lymphoma cells, we found that MGd induced HO-1 up to 8 fold by 24 hrs and that longer incubations did not result in appreciably greater amounts of protein. HO-1 levels returned to baseline in Ramos cells 48 hrs after cells were cultured in fresh media in the absence of MGd. HO-1 levels were elevated at baseline in HF-1 cells (compared to Ramos) and increased about 2 fold with MGd treatment. Other metallotexaphyrins, europium texaphyrin and dysprosium texaphyrin, also induced HO-1 expression. To determine if HO-1 expression was important for cell survival, we co-treated cells with MGd and tin protoporphyrin (SnPP), an inhibitor of HO-1 enzymatic activity. We found that both HF-1 and Ramos cells were sensitized to MGd-induced cell death by SnPP. These results demonstrate for the first time that metallotexaphyrins can upregulate HO-1 expression. The induction of HO-1 could be related to oxidative stress and/or metallotexaphyrins acting as heme mimetics.

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Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/937370 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Yan Wang ◽

Wen-Liang Pan ◽

Wei-Cheng Liang ◽

Wai-Kit Law ◽

Denis Tsz-Ming Ip ◽

...

Keyword(s):

Heme Oxygenase ◽

Apoptotic Cell ◽

Acetylcholinesterase Inhibitors ◽

Docking Study ◽

Ache Inhibitor ◽

Heme Oxygenase 1 ◽

Mitochondria Membrane Potential ◽

Aloe Emodin ◽

Angelicae Dahuricae Radix ◽

First Time

Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, andβ,β-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 μM. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells.

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