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Background: Although both chemotherapy and radiotherapy (RT) can sufficiently maintain tumor suppression of colorectal cancer (CRC), these treatments may trigger the expression of nuclear factor kappa B (NF-κB) and compromise patients' survival. Regorafenib suppresses NF-κB activity in various tumor types. However, whether regorafenib may act as a suitable radiosensitizer to enhance therapeutic efficacy of RT remains unknown., Materials and Methods: Here, we established a CRC-bearing animal model to investigate the therapeutic efficacy of regorafenib in combination with RT, through measurement of tumor growth, body weight, whole-body computed tomography (CT) scan and immunohisto-chemistry staining., Results: Smallest tumor size and weight were found in the combination treatment group. In addition, RT-induced up-regulation of NF-κB and downstream proteins were diminished by regorafenib. Moreover, the body weight and liver pathology in the treated group were similar to those of the non-treated control group., Conclusion: Regorafenib may enhance the anti-CRC efficacy of RT., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Quetiapine, an atypical antipsychotic, has been encountered as a potential protective agent to suppress various types of tumor growth. However, the inhibitory mechanism of quetiapine in hepatocellular carcinoma (HCC) still remains unclear. The purpose of present study was to investigate the inhibitory mechanism of quetiapine on cell survival and invasion in HCC., Materials and Methods: Changes of apoptotic signaling, migration/invasion ability, and signaling transduction involved in cell survival and invasion were evaluated with flow cytometry, migration/invasion, and western blot assays., Results: Quetiapine inhibited cell proliferation and migration/invasion in SK-Hep1 and Hep3B cells. Quetiapine induced extrinsic and intrinsic apoptotic pathways. Activation of extracellular signal-regulated kinases (ERK), protein kinase B (AKT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), expression of anti-apoptotic, and metastasis-associated proteins were decreased by quetiapine., Conclusion: The apoptosis induction, the decreased expression of ERK/AKT-mediated anti-apoptotic and the metastasis-associated proteins were associated with quetiapine-inhibited cell survival and invasion in HCC in vitro., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: The aim of the present study was to confirm therapeutic efficacy and find probable mechanism of action of amentoflavone in hepatocellular carcinoma (HCC) in vivo., Materials and Methods: Luciferase reporter vector pGL4.50_transfected SK-Hep1 (SK-Hep1/luc2) tumor-bearing mice were treated with vehicle or amentoflavone (100 mg/kg/day by gavage) for 14 days. Tumor growth, amentoflavone toxicity, and extracellular signal-regulated kinase (ERK)/nuclear factor-kappaB (NF-ĸB) signaling in tumor progression were evaluated with digital caliper, bioluminescence imaging, computed tomography, body weight, pathological examination of liver, and immunohistochemistry staining., Results: Amentoflavone significantly inhibited tumor growth, ERK/NF-ĸB activation, and expression of tumor progression-associated proteins as compared to vehicle-treated group. In addition, body weight and liver morphology of mice were not influenced by amentoflavone treatment., Conclusion: These results suggest that amentoflavone inhibits HCC progression through suppression of ERK/NF-ĸB signaling., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: A previous study indicated that amentoflavone inhibits tumor growth of breast cancer. However, the anti-cancer effects and mechanism of amentoflavone in hepatocellular carcinoma (HCC) have not been elucidated. The aim of the present study was to verify the effect of amentoflavone on tumor progression in HCC., Materials and Methods: HCC SK-Hep1 cells were treated with different concentrations of amentoflavone or 10 μM PD98059 (extracellular signal-regulated kinases (ERK) inhibitor) for 48 h, respectively, and then cell viability, NF-κB activation, levels of tumor progression-associated proteins, and cell invasion were evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), NF-κB reporter gene assay, western blotting, and cell invasion assay., Results: The results demonstrated that both amentoflavone and PD98059 not only significantly reduced cell viability, NF-κB activation, and cell invasion, but also inhibited the expression of tumor progression-associated proteins. In addition, we found that amentoflavone suppresses ERK phosphorylation., Conclusion: The results of the present study suggest that amentoflavone down-regulates ERK-modulated tumor progression in HCC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The goal of the present study was to investigate anticancer effect of amentoflavone on glioblastoma cells in vitro. Our results demonstrated that amentoflavone not only significantly reduced cell viability, nuclear factor-ĸappa B (NF-ĸB) activation, and protein expression of cellular Fas-associated protein with death domain-like interleukin 1 beta-converting enzyme inhibitory protein (C-FLIP) and myeloid cell leukemia 1 (MCL1), but significantly triggered cell accumulation at the sub-G 1 phase, loss of mitochondrial membrane potential, and expression of active caspase-3 and -8. In order to verify the effect of NF-ĸB inhibitor on expression of anti-apoptotic proteins, we performed western blotting. We found that the of NF-ĸB inhibitor or amentoflavone markedly diminished protein levels of MCL1 and C-FLIP. Taken all together, our findings show that amentoflavone induces intrinsic and extrinsic apoptosis and inhibits NF-ĸB-modulated anti-apoptotic signaling in U-87 MG cells in vitro., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Exposure to ultraviolet (UV) light is closely related to human diseases, such as skin cancer, due to irreversible injuries to the skin cells. The UV-induced DNA damage and programmed cell death are important determinants for skin carcinogenesis. The aim of the present study was to investigate the anti-ultraviolet-C (UVC) effects of pyridoxamine in human keratinocyte HaCaT cells and its mechanisms of action., Results: UVC-induced programmed cell death in HaCaT cells was abrogated by treated the cells immediately after UVC irradiation with 40, 80 and 160 μM of pyridoxamine. Monitoring the UVC-induced-specific reactive oxygen species, we found that 20, 40, 80 and 160 μM of pyridoxamine was also effective in suppressing the induction of reactive oxygen species by UVC., Conclusion: Overall, our results provided evidence showing that pyridoxamine was effective in protecting HaCaT cells from UVC-induced programmed cell death and may be a potential anti-UVC agent in life and clinical practice., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Long-term exposure to solar ultraviolet (UV) radiation can cause multiple skin disorders, including skin cancer. Protection against UV-induced damage is, therefore, a worldwide concern. Baicalin, a major component of traditional Chinese medicine Scutellaria baicalensis, has been reported to have antioxidant and cytostatic effects on normal epithelial and normal peripheral blood and myeloid cells. In the current study, we examined whether baicalin could also effectively protect human keratinocytes from damaging short-wave UVC irradiation. Baicalin-scavenged reactive oxygen species increased within 2 h after UVC radiation. Baicalin also abrogated UVC-induced apoptosis. In addition, we identified the major products after UVC radiation with T4 UV endonuclease, finding that baicalin prevented cyclobutane pyrimidine dimer formation induced by UVC. Furthermore, baicalin also prevented formation of oxidative adducts induced by UVC. Our results demonstrated the utility of baicalin in assessing the potential contribution of traditional Chinese medicinal agents in therapy of UVC-induced genomic damage to skin and suggest potential application of these agents as pharmaceuticals in prevention of solar-induced skin damage.

Amentoflavone, isolated from an ethyl acetate extract of the whole plant of Selaginella tamariscina, a traditional herb, may exhibit antitumor activity. The aim of this study was to investigate the anticancer mechanism(s) of amentoflavone, such as mitochondria-mediated apoptotic cell death, in typical breast cancer MCF-7 cells. Cells treated with amentoflavone exhibited a series of cellular alterations related to apoptosis, including DNA and nuclear fragmentation, and de-regulation of intracellular reactive oxygen species (ROS) and calcium. In addition, markers of mitochondrial-mediated apoptosis, including the reduction of mitochondrial inner-membrane potential, the release of cytochrome c from mitochondria, and activation of caspase 3, were observed. In conclusion, our results present, to our knowledge, the first evidence that amentoflavone induces apoptosis of MCF-7 breast cancer cells, and that this is closely related to mitochondrial dysfunction. Amentoflavone may be a potential therapeutic agent for breast cancer treatment.

Ultraviolet (UV) radiation is a natural insult to various organisms. Earthworms, although possessing similar biomolecules to those in mammalian skin, do not suffer from skin cancer nor any other types of cancer as humans do. However, little is known about the molecular mechanism of the earthworm's tolerance to UV. In this study, we evaluated the genotoxicity of UV and the capacity of earthworm cell to repair UV-induced damage. The T4 UV endonuclease UV-incorporated comet assay was used to examine the excision and rejoining steps of UV-induced pyrimidine dimer. Earthworm testis cells were treated with a combination of 5 mM hydroxyurea plus 50 μM cytosine-β-D-arabinofuranoside for 6 h to block DNA rejoining capacity and to investigate excision dynamics. Compared with H(2)O(2)-induced oxidative repair capacity, the excision step of repair of UV-induced lesions in earthworm testis cells was significantly lower. After 6-h treatment of 5 mM hydroxyurea plus 50 μM cytosine-β-D-arabinofuranoside, the medium was totally replaced with fresh medium and cells were allowed to rejoin the accumulated DNA strand breaks. We found that the capacity for rejoining UV-induced breaks was also significantly lower than that for the H(2)O(2)-induced breaks. Our results strongly suggest that earthworms seem to be efficient at repairing H(2)O(2)-induced oxidative DNA adducts, but not so capable of removing UV-induced pyrimidine dimers from their genome.

Curcumin (diferuloylmethane), a phenolic compound from the plant Curcuma longa (Linn.) has been shown to exhibit antitumor activity and apoptosis in many human cancer cell lines including that of lung and liver cancer. In this study, curcumin was evaluated in BALB/c mice for its ability to inhibit pulmonary and liver adenoma formation and growth after they were orally treated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Animals were treated with DHPN in water for approximately 14 days before multiple doses of curcumin were given intraperitoneally. It was found that 200 microM curcumin reduced lung and liver tumor multiplicity by 37% (p<0.05) and 30% (p<0.05) respectively. The results indicated that curcumin significantly inhibited pulmonary and liver adenoma formation and growth in BALB/c mice. The precise mechanism by which curcumin inhibits lung and liver tumorigenesis remains to be elucidated. Thus, curcumin appears to be a promising new chemotherapeutic and preventive agent for lung and liver cancer induced by DHPN.

The effects of oral luteolin on the N-acetylation and metabolism of 2-aminofluorene (AF) in vivo were investigated in bladder, blood, colon, kidney, liver, feces, urine, cerebrum, cerebellum and pineal gland from male Sprague-Dawley rats. Major metabolites such as AAF, 1-OH-AAF, 3-OH-AAF, 8-OH-AAF and 9-OH-AAF were found in bladder tissues; AAF, 1-OH-AAF, 5-OH-AAF and 8-OH-AAF were found in blood samples; AAF, 1-OH-AAF, 3-OH-AAF, 5-OH-AAF, 8-OH-AAF and 9-OH-AAF were found in colon tissues; AAF, 1-OH-AAF, 3-OH-AAF and 9-OH-AAF were found in kidney tissues; AAF, 1-OH-AAF, 3-OH-AAF and 8-OH-AAF were found in liver tissues, AAF, 1-OH-AAF, 3-OH-AAF, 5-OH-AAF, 7-OH-AAF, 8-OH-AA and 9-OH-AAF were found in feces and urine samples; AAF, 1-OH-AAF, 3-OH-AAF and 8-OH-AAF were found in cerebrum tissues; AAF, 1-OH-AAF, 3-OH-AAF and 7-OH-AAF were found in cerebellum tissues; but only AF and AAF were found in pineal gland in rats treated with AF (50 mg/kg) for 24 h. Pretreatment of rats with luteolin (30 mg/kg) 24 h prior to the administration of AF (50 mg/kg) and luteolin given with AF concomitantly led to a decrease in the amounts of 3-OH-AAF and 9-OH-AAF and an increase in the amounts of 1-OH-AAF and 8-OH-AAF in bladder tissues. In blood samples, there were significant decreases of AAF, 1-OH-AAF and 8-OH-AAF after rats were treated with luteolin for 24 h prior to AF but luteolin with AF at the same time caused an increase in 1-OH-AAF. In colon tissues, there were significant decreases of AF, 1-OH-AAF, 3-OH-AAF, 5-OH-AAF and 9-OH-AAF after rats were treated with luteolin for 24 h then AF but the amounts of AF, 1-OH-AAF, 5-OH-AAF and 9-OH-AAF decreased and AAF and 8-OH-AAF increased in rats treated with luteolin and AF at the same time. In kidney tissues, there were significant decreases of AF, AAF and 3-OH-AAF after rats were treated with both compounds at the same time, but luteolin for 24 h then AF treatment led to significant decreases of 3-OH-AAF. In liver samples, after rats were treated with luteolin and AF at the same time, the amounts of AAF and 1-OH-AAF significantly decreased but 8-OH-AAF increased. However, rats treated with luteolin for 24 h then with AF led to significant decreases of AAF, 1-OH-AAF and 3-OH-AAF. In feces samples, there were significant increases of AAF, 3-OH-AAF, 7-OH-AAF, 8-OH-AAF and 9-OH-AAF after rats were treated with both compounds at the same time but luteolin for 24 h then AF treatment led to a significant increase of AF, 1-OH-AAF and 8-OH-AAF and a decrease AAF and 3-OH-AAF. In urine samples, there were significant increases of AF, AAF, 1-OH-AAF, 3-OH-AAF, 5-OH-AAF and 9-OH-AAF but a decrease of 8-OH-AAF after rats were treated with both compounds at the same time. However, the luteolin for 24 h then AF treatment led to significant increases of AF, AAF and 1-OH-AAF but decreases of 3-OH-AAF and 5-OH-AAF. In cerebrum samples, there were significant increases ofAF but decreases of 1-OH-AAF and 8-OH-AAF after rats were treated with both compounds at the same time; luteolin for 24 h then AF treatment of rats led to significant increase of 1-OH-AAF and decreases AF, AAF and 8-OH-AAF. In cerebellum samples, there were significant increases of AAF and decreases of 1-OH-AAF and 3-OH-AAF after rats were treated with both compounds at the same time, there is a significant increase of AAF but decrease of 1-OH-AAF, 3-OH-AAF and 7-OH-AAF after the luteolin treated for 24 h then AF were treated to the rats. In pineal gland samples, there were significant increases ofAAF after rats were treated with both compounds at the same time. However, luteolin treated for 24 h then AF were treated to the rats which increase AAF but decrease AF.

Berberine, a yellow benzylisoquinoline alkaloid, is a constituent of Coptis chines and is commonly used in Chinese herbal medicine for patients with gastrointestinal disorders. The pharmacological effects of berberine include anti-inflammation, antidiarrhetic, antimalarial, and even antimicrobial activities. However, its mechanism of action on the cell migration of human gastric cancer SNU-5 cells is not fully understood. The effects of berberine on the percentage of viable cells were examined first and it was found that berberine induced dose-dependent inhibition in human gastric cancer SNU-5 cells. The effect of berberine on the levels of reactive oxygen species (ROS) and matrix metalloproteinase-1, -2, -7 and -9 was then examined using Western blotting and the results showed that berberine induced ROS production for up to 6 hours of incubation. It was also found that berberine induced downregulation of MMP-1 -2, and -9 but did not affect the level of MMP-7. The mRNA levels of MMPs in SNU-5 cells after treatment with berberine for 24 hours were investigated using a polymerase chain reaction and the results showed that berberine inhibited the gene expression of MMP-1, -2 and -9 in human SNU-5 cells but it did not affect MMP-7. In conclusion, berberine appears to exert its anticancer properties by inducing ROS production and prevention of cell migration via inhibition of the gene expression of MMP-1, -2 and -9 in human gastric cancer SNU-5 cancer cells.

Curcumin (1, 7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5- dione), a natural polyphenol product of the plant Curcuma longa, exhibited potent inhibitory activities against proliferation, induced cell cycle arrest and exhibited the induction of apoptosis in several tumor cell lines. In our previous studies, we have shown that curcumin induced cell cycle arrest and apoptosis on human leukemia HL-60 and mouse leukemia WEHI-3 cells; there are no reports regarding whether or not it affects leukemia cells in vivo. In the present study, we investigated the effects of curcumin on WEHI-3 in BALB/c mice and the results indicated that curcumin reduces the percentage of Mac-3 marker, which is the precursor of macrophage. Curcumin induced significant effects on the population of B cells from murine leukemia in vivo. We also investigated the weights of spleen and liver from murine leukemia and the results showed that curcumin reduced the weight of the liver and spleen. From the pathological examinations, the effects of curcumin on the liver and spleen from mice after being injected with WEHI-3 cells were apparent. Both organs were enlarged. In conclusion, curcumin affect WEHI-3 cells in vivo.

Aloe-emodin has shown anti-neoplastic activity against some human cancer cell lines. This study aimed to explore the effects of aloe-emodin on the phagocytosis of macrophages, the activity of natural killer (NK) cells and the expression of cytokines in leukocytes from Sprague-Dawley rats. Leukocytes were collected, placed into culture plates and the functions of macrophages and NK cells and the percentage of viable cells were determined by flow cytometric analysis. Incubation of leukocytes with various concentrations of aloe-emodin caused a dose-dependent decrease of viable cells, a decrease of phagocytosis by macrophages, and a decrease of the activity of NK cells. Evaluation of cytokines in leukocytes by ELISA indicated that aloe-emodin increased the levels of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. The results were also confirmed by PCR assay for the mRNA expression of the examined cytokines.

The present study was undertaken to determine the effect of acetylsalicylic acid acid on the in vitro N-acetyltransferase (NAT) enzyme activity and in vivo acetylation of 2-aminofluorene in laboratory rats. In the in vitro experiments, cytosols of blood, bladder, colon and liver cells, with or without acetylsalicylic acid co-treatment, showed different percentages of 2-aminofluorene acetylation. The data indicated that there was decreased NAT activity associated with increased acetylsalicylic acid in the cytosol reaction. In the in vitro experiments, values of apparent Km and Vmax decreased by 4% and 21%, respectively, for acetylation of AF in blood NAT, 28% and 31% for acetylation of AF in bladder NAT, 12% and 25% for acetylation of AF in colon NAT, and 50% and 35% for acetylation of AF in liver NAT. In the in vivo experiments, pretreatment with acetylsalicylic acid (50 mg/kg) 48 h prior to the administration of 2-aminofluorene (50 mg/kg) resulted in 24% and 28% decreases in the fecal and urinary recovery of N-acetyl-2-aminofluorene and a 26% decrease in the metabolic clearance of 2-aminofluorene to N-acetyl-2-aminofluorene. This is the first demonstration of acetylsalicylic acid (Aspirin) inhibition of arylamine N-acetyltransferase activity showing decreases in the N-acetylation of carcinogens in vivo.

Background: The effects of 5-methoxypsoralen (5-MOP) on the distribution and metabolism of chemical carcinogens such as 2-aminofluorene (AF) has not been previously reported. In this study, the influences of 5-MOP on the metabolism of AF in Sprague-Dawley (SD) rats were investigated., Materials and Methods: After receiving 5-MOP in 24 hours, AF was introduced into each animal by gastric intubation. After 12, 24, 48 and 72 hours the urine, feces, and cytosol of the liver, kidneys, stomach, colon, bladder and blood of rats were collected and assayed for AF and its metabolites by HPLC., Results: Compared to the control regimen, 5-MOP caused an increase of the metabolites excreted in urine and feces. The largest dose of metabolites were excreted between 48-72 hours. The major metabolite excreted in the urine was 9-hydroxy-AAF (9-OH-AAF) and in the feces was 7-hydroxy-AAF (7-OH-AAF). There was no time-effect for the tissues, and the liver was the main target organ for the AF and its metabolites. The major residual metabolite of AF in the liver, kidneys, stomach, colon and bladder was 7-OH-AAF. In blood it was 9-OH-AAF. The bladder had the lowest metabolic residue in tissues, and blood played the role of transportation but was not the target organ. 5-MOP decreased the concentration of AF and its residual metabolites of liver, stomach, kidneys, bladder and blood at various times., Conclusion: 5-MOP increased the metabolism of AF in order to transform to ring-hydroxylated metabolites and increased excretion of the ring-hydroxylated metabolites, therefore decreasing AF and its residual metabolites in vivo. Although 5-MOP was shown to be an inhibitor of CYP 2A6 and CYP 2B1, somehow it causes an increase of activity in AF metabolism in vivo; it induces more CYPs involved in the metabolism of AF.