Prevention of Carcinogenesis and Development of Gastric and Colon Cancers by 2-Aminophenoxazine-3-one (Phx-3):  Direct and Indirect Anti-Cancer Activity of Phx-3

Tomoda, Akio; Miyazawa, Kenji; Tabuchi, Takafumi

doi:10.3390/ijms140917573

Cited by 7 publications

(7 citation statements)

References 53 publications

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“…This potassium-sparing diuretic, apart from having a direct antitumoral, antimetastatic and antiangiogenic effect [ 283 , 285 , 286 ], at least in part by inhibiting uPA and VEGF, has been shown to be well tolerated and safe when used in the chronic situation in pharmacological dosages in humans, the main side-effect being occasionally increased plasma K + levels [ 284 , 287 , 288 ]. Since more selective and powerful NHE inhibitors, like Cariporide, Phx-3 and compound 9t are not available for human use [ 19 , 289 , 290 ], amiloride should still be part of new protocols dealing with the concerted use of a cocktail of proton transport inhibitors (PTIs) as anticancer agents in different human solid tumors [ 85 , 284 , 291 ].…”

Section: Anticancer and Antimetastatic Potential Of The New And Potenmentioning

confidence: 99%

Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

et al. 2014

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Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then proposea new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced.

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Section: Anticancer and Antimetastatic Potential Of The New And Potenmentioning

confidence: 99%

Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

et al. 2014

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“…Among these studies, we excluded 3 studies for not using PCR to detect Helicobacter species (the culture method was used). 23 – 25 Three additional studies were excluded for not reporting useful results to calculate the RR: 1 study included patients with other bowel diseases and did not report the exact number of patients with IBD, 26 a 2nd study was excluded because the author did not reply to our enquiry email, 27 and a 3rd article focused on T-cell clones instead of Helicobacter strains. 28 Our meta-analysis included 14 studies that evaluated 1407 individuals.…”

Section: Resultsmentioning

confidence: 99%

Enterohepatic Helicobacter Species as a Potential Causative Factor in Inflammatory Bowel Disease

Zhang²,

Li³

et al. 2015

Medicine

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The Helicobacter species in the gut microbiota comprise Helicobacter pylori (H pylori) and enterohepatic Helicobacter species (EHS), which can colonize the intestinal mucosa. However, it is unclear whether EHS are associated with inflammatory bowel disease (IBD). Therefore, we conducted this meta-analysis to examine the association between EHS and IBD.PubMed, Scopus, Cochrane Library, and Web of Science databases, as well as abstracts from conference proceedings were searched to identify studies that used polymerase chain reaction to detect Helicobacter species in intestinal samples from patients with IBD.After screening, we carefully reviewed 20 of the 2955 identified studies, and performed a meta-analysis of the findings from 14 studies (11 adult studies and 3 pediatric studies) using STATA v12.0. These studies evaluated 1407 individuals, including 433 patients with Crohn's disease, 306 patients with ulcerative colitis, and 668 controls. The prevalence of Helicobacter species was higher among the patients with IBD, compared to that among the controls, which corresponded to a pooled risk ratio (RR) of 1.59 (95% confidence interval [CI]: 1.12–2.27). The RRs for adult and pediatric patients with IBD were 1.61 (95% CI: 1.03–2.52) and 1.76 (95% CI: 1.17–2.64), respectively. Compared to the controls, the patients with IBD tended to have a higher prevalence of EHS in the intestinal mucosa (RR: 2.01, 95% CI: 1.36–2.98), although the prevalence of H pylori was not significantly higher (RR: 1.22, 95% CI: 0.77–1.95). Compared to the controls, the RRs for EHS in patients with Crohn's disease and ulcerative colitis were 1.72 (95% CI: 1.20–2.47) and 3.27 (95% CI: 0.93–11.44), respectively.It appears that EHS was associated with IBD, while intestinal H pylori infection was not significantly associated with IBD. Further studies are needed to determine the involvement of EHS in the microbiological etiology of IBD.

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“…Questiomycin A was demonstrated as costive agent of apoptotic cell death in the gastric and colon cancer cell line by dysregulating the function of mitochondria, and activating the caspase signaling [ 68 , 69 , 74 ]. Questinomycin A also induced cellular apoptosis by causing rapid intracellular acidification in several cancer cells [ 69 , 70 , 72 , 74 ], generating reactive oxygen species in human lung adenocarcinoma cells and human glioblastoma cell line [ 71 , 72 ] and by DNA laddering and upregulated Fas expression in mouse melanoma B16 cells [ 75 ]. Direct connection of Questiomycin with p53 still remains an issue to be elucidated.…”

Section: Perspective and Conclusionmentioning

confidence: 99%

Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

et al. 2018

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The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X2 are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound (Ki in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D's action on tumors and suggests new avenues and molecules for medical applications.

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Prevention of Carcinogenesis and Development of Gastric and Colon Cancers by 2-Aminophenoxazine-3-one (Phx-3): Direct and Indirect Anti-Cancer Activity of Phx-3

Cited by 7 publications

References 53 publications

Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

Enterohepatic Helicobacter Species as a Potential Causative Factor in Inflammatory Bowel Disease

Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

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