Quantification of Hormesis in Anticancer-Agent Dose-Responses

Nascarella, Marc A.; Stanek, Edward J.; Hoffmann, George; Calabrese, Edward J.

doi:10.2203/dose-response.08-025.nascarella

Cited by 18 publications

(7 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additive, synergistic or antagonistic mutual interactions of two drugs can be quantified within the quasilinear region of the dose-effect-curves using the median effect principle of Chou [24] or the unified response surface area of Greco et al [25] . However the interactions of drug combination is difficult to quantify for hormetic dose-response-relations [26] . There are various models to assess hormesis for a single drug treatment [27] , [28] .…”

Section: Resultsmentioning

confidence: 99%

Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

et al. 2011

View full text Add to dashboard Cite

BackgroundOmeprazole has recently been described as a modulator of tumour chemoresistance, although its underlying molecular mechanisms remain controversial. Since pancreatic tumours are highly chemoresistant, a logical step would be to investigate the pharmacodynamic, morphological and biochemical effects of omeprazole on pancreatic cancer cell lines.Methodology/Principal FindingsDose-effect curves of omeprazole, pantoprazole, gemcitabine, 5-fluorouracil and the combinations of omeprazole and 5-fluorouracil or gemcitabine were generated for the pancreatic cancer cell lines MiaPaCa-2, ASPC-1, Colo357, PancTu-1, Panc1 and Panc89. They revealed that omeprazole inhibited proliferation at probably non-toxic concentrations and reversed the hormesis phenomena of 5-fluorouracil. Electron microscopy showed that omeprazole led to accumulation of phagophores and early autophagosomes in ASPC-1 and MiaPaCa-2 cells. Signal changes indicating inhibited proliferation and programmed cell death were found by proton NMR spectroscopy of both cell lines when treated with omeprazole which was identified intracellularly. Omeprazole modulates the lysosomal transport pathway as shown by Western blot analysis of the expression of LAMP-1, Cathepsin-D and β-COP in lysosome- and Golgi complex containing cell fractions. Acridine orange staining revealed that the pump function of the vATPase was not specifically inhibited by omeprazole. Gene expression of the autophagy-related LC3 gene as well as of Bad, Mdr-1, Atg12 and the vATPase was analysed after treatment of cells with 5-fluorouracil and omeprazole and confirmed the above mentioned results.ConclusionsWe hypothesise that omeprazole interacts with the regulatory functions of the vATPase without inhibiting its pump function. A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death. This may circumvent common resistance mechanisms of pancreatic cancer. Since omeprazole use has already been established in clinical practice these results could lead to new clinical applications.

show abstract

Section: Resultsmentioning

confidence: 99%

Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…A marked increase in microvessel formation at lower doses between 0.625-1.25 µM was also observed. This bell-shaped effect (hormesis) is common in anticancer agents (15,42) which suggests the importance of maintaining the SFN at high concentrations (>5 µM) for cancer chemoprevention or treatment. These tube formation results were consistent with the cell viability data that showed that SFN inhibited the growth of ECs at concentrations of 5-20 µM while at low concentrations of 0.625-2.5 µM, SFN promoted cell growth.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

et al. 2017

View full text Add to dashboard Cite

Abstract. Aberrant neovascularization supports nutrients and the oxygen microenvironment in tumour growth, invasion and metastasis. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of vascular conditions. Sulforaphane (SFN), an isothiocyanate, has been reported to possess chemopreventive properties. In the present study, the effects of SFN on cell proliferation and tubular formation have been investigated using endothelial cells (ECs) and pericytes in coculture. SFN showed a dosedependent inhibition on the growth of ECs and pericytes with IC 50 values 46.7 and 32.4 µM, respectively. SFN (5-20 µM) inhibited tube formation in a 3D coculture although a lower dose (1.25 µM) promoted 30% more endothelial tube formation than control. Moreover, SFN affected intercellular communication between ECs and pericytes via inhibition of angiogenic factor such as vascular endothelial growth factor (VEGF) expression in pericytes. However, the expression of its receptor (VEGFR-2) was found significantly increased in ECs. These effects were associated with downregulation of prolyl hydroxylase domain-containing protein 1 and 2 (PHD1/2) and activation of hypoxia-inducible factor-1 (HIF) pathway by SFN. Furthermore, thioredoxin reductase-1 was also upregulated by SFN treatment, suggesting that antioxidant and redox regulation are involved in angiogenesis. Taken together, the results of the present study suggest that SFN differentially regulates endothelial cells and pericytes disrupting their interplay through the VEGF-VEGFR signalling pathway. Anti-angiogenesis property of SFN indicates that it has potential role as an anticancer agent. IntroductionAngiogenesis, the growth of new capillary blood vessels, is a normal and vital process in growth, development and wound healing. However, it is also a fundamental step in the growth of tumours. Nutrients and oxygen, supplied by the blood vessels into the tumours, are essential for the growth and progression of malignant tumours beyond the size of 1-2 mm 3 (1). Newly formed blood vessels can facilitate cells escaping through leakage from primary tumour sites to metastasize, the major cause of mortality for cancer patients. Anti-angiogenesis has been recognized as valuable therapy in treatment of various metastatic cancers since the theory was first proposed by Folkman (2,3). Tumour angiogenesis is believed to be regulated by the interactions between pro-angiogenic and anti-angiogenic factors in the tumour microenvironment (4). Angiogenic response is a dynamic process requiring a series of fine-tuned angiogenic signalling and molecular events. Hypoxia is the common inducer of angiogenesis in the core of large tumours stimulating the release of pro-angiogenic factors to promote endothelial cell proliferation, migration, differentiation and self-assembly into vascular-like structures. Subsequently, perivascular cells are recruited to form mature and stable vessels (5).The interaction between endothelial cells (ECs) and pericytes (PVCs) has g...

show abstract

“…However, in another context, these compounds may be of use as anticancer agents instead. Notably, however, they display the phenomenon of 'hormesis', a term widely used by toxicologists to describe a biphasic dose response to a drug, with stimulatory effects at low dose and inhibition at higher doses; thought to be an adaptive compensatory response to initial disruption of cellular homeostasis (31,32). At low doses a drug could block an endogenous inhibitory factor, resulting in stimulation, before it starts to exert its own inhibitory effect on other pathways at higher concentration.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative activity of a series of 5-(1H-1,2,3-triazolyl) methyl- and 5-acetamidomethyl-oxazolidinone derivatives

Hedaya

Mathew

Mohamed

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

In the face of increasing resistance to the existing antibiotics, oxazolidinones (exemplified by linezolid) have been developed as promising antibacterial agents, but may have other useful actions. In the present study, a series of 5‑(1H‑1,2,3‑triazoly) l‑methyl‑, 5‑acetamidomethyl‑morpholino and N‑substituted‑piperazino oxazolidinone derivatives were investigated to determine whether they are active against eukaryotic cells. An MTT assay, validated by cell counting, was used to assess the effect of nine oxazolidinone derivatives (concentrations 100 nM‑10 µM) on the proliferation of MCF7 human breast cancer cells. The three most active compounds were then tested on MDA231 breast cancer cells. Cytotoxicity of the selected derivatives was determined by assessing the extent of apoptosis by flow cytometry. The antimetastatic potential of these compounds was assessed on MDA231 cells using wound healing and agarose invasion assays. The 5‑triazolylmethyl piperazino‑oxazolidinone derivatives containing 4‑N‑(2‑chlorocinnamoyl), 4‑N‑(4‑nitrobenzoyl) and 4‑N‑methylsulfonyl moieties exhibited the most potent cytostatic activity against cancer, inhibiting proliferation by up to 70%, in the same order as their reported antibacterial activity against Staphylococcus aureus, but at higher concentrations. Unexpectedly, several derivatives stimulated proliferation at 100 nM, well below their antibacterial minimum inhibitory concentrations. Certain compounds also retarded the motility and invasion of MDA231 cells. Three of the tested derivatives had no effect on the eukaryotic cell lines, demonstrating their preferential activity against bacteria. Two compounds actually stimulated eukaryotic cell proliferation. The remaining three exhibited potent cytostatic activity against and cancer cells, displaying differences in response at low and high concentrations, which may suggest multiple targets on eukaryotic cells. These latter compounds may be useful as anticancer agents.

show abstract

Quantification of Hormesis in Anticancer-Agent Dose-Responses

Cited by 18 publications

References 11 publications

Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

Antiproliferative activity of a series of 5-(1H-1,2,3-triazolyl) methyl- and 5-acetamidomethyl-oxazolidinone derivatives

Contact Info

Product

Resources

About