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Indian Journal of Pharmacology 2023Colon carcinoma stands as the most familiar malignancy throughout across the globe. Raptinal induce apoptosis through the alteration of cellular events. Thus, in the...
OBJECTIVES
Colon carcinoma stands as the most familiar malignancy throughout across the globe. Raptinal induce apoptosis through the alteration of cellular events. Thus, in the present investigation, the anticancer activity of raptinal counter to 1,2-dimethylhydrazine (DMH) persuaded colon carcinoma has been evaluated through both in vivo and in vitro systems.
MATERIALS AND METHODS
The pharmacophore analysis demonstrated the binding efficacy of raptinal with the apoptotic proteins. The chemotherapeutic activity of raptinal was examined through HT-29 human colorectal cancer (CRC) cell line as well as DMH persuaded CRC in the rat model. The cytotoxicity analysis, flow cytometry, and DAPI analysis have been carried out on HT-29 cell line through in vitro assessment. The colon carcinoma has been induced through DMH administration and subsequently Dextran sulfate sodium treatment in male Wistar rats. After 18 weeks of raptinal treatment, the colon tissues have been investigated for aberrant crypt foci (ACF) count, antioxidant status, histology, immunohistochemical assessment, and apoptotic analysis.
RESULTS
The raptinal therapy on HT-29 cells demonstrated a substantial % of early apoptosis followed by G0 and G1 phase arrest, which subsequently led to apoptosis. Furthermore, it inhibits ACF development with improved colonic abrasions and structural integrity of colonic mucosa with increased levels of antioxidants, proapoptotic biomarkers including p53, caspase-3, Bax and downstream effects of Bcl-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 mutation.
CONCLUSIONS
These findings indicate the raptinal effectively reduces colon cancer by inducing apoptosis through p53/Bcl2/Bax/caspase-3 pathway and suppressing IL-6, TNF-mediated chronic inflammation in the colon cancer microenvironment.
Topics: Humans; Male; Animals; Rats; Rats, Wistar; 1,2-Dimethylhydrazine; Tumor Suppressor Protein p53; bcl-2-Associated X Protein; Caspase 3; Colonic Neoplasms; Antioxidants; Carcinoma; Tumor Microenvironment
PubMed: 37313935
DOI: 10.4103/ijp.ijp_168_22 -
IUBMB Life Jul 2009The serum and glucocorticoid inducible kinase SGK1 was originally cloned from mammary tumor cells. SGK1 was found to be up-regulated in a variety of tumors, but...
The serum and glucocorticoid inducible kinase SGK1 was originally cloned from mammary tumor cells. SGK1 was found to be up-regulated in a variety of tumors, but down-regulated in several distinct tumors. Thus, evidence for a role of SGK1 in tumor growth remained conflicting. According to in vitro observations, SGK1 is up-regulated by the oncogene beta-catenin and negatively regulates the proapoptotic transcription factor FOXO3a, which in turn stimulates transcription of the Bcl2-interacting mediator BIM. This study aimed to define the role of SGK1 in colon carcinoma in vivo. SGK1 knockout mice (sgk1(-/-)) and their wild type littermates (sgk1(+/+)) were subjected to chemical cancerogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium for 7 days). Moreover, SGK1 was silenced in HEK293 cells. FOXO3a and BIM protein abundance was determined by Western blotting and immunohistochemistry. Following chemical cancerogenesis, sgk1(-/-)mice developed significantly less colonic tumors than sgk1(+/+)mice. According to Western blotting and immunohistochemistry, SGK1 deficiency enhanced the expression of FOXO3a and BIM both, in vitro and in vivo. SGK1 deficiency counteracts the development of colonic tumors, an effect at least in part due to up-regulation of FOXO3a and BIM.
Topics: 1,2-Dimethylhydrazine; Animals; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Cell Hypoxia; Colonic Neoplasms; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immediate-Early Proteins; Kidney; Membrane Proteins; Mice; Mice, Knockout; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Tumor Cells, Cultured
PubMed: 19548318
DOI: 10.1002/iub.209 -
Asian Pacific Journal of Cancer... Jul 2020Aberrant Crypt (AC) and Aberrant Crypt Focus (ACF) are considered pre-neoplasic lesions, ranging from hyperplasia to different degrees of dysplasia in the colon. This...
INTRODUCTION
Aberrant Crypt (AC) and Aberrant Crypt Focus (ACF) are considered pre-neoplasic lesions, ranging from hyperplasia to different degrees of dysplasia in the colon. This work aimed to evaluate and quantify the chemopreventive activity of Zingiber officinale essential oil in the colorectal region of Wistar rats.
MATERIALS AND METHODS
We extracted the essential oil from ginger rhizomes and carried out ACF induction, in rats, with 1.2 Dimethylhydrazine (DMH) at a 20 mg/kg dose. The experimental groups were GI (negative control); GII (positive induction control); GIII (DMH + essential oil); GIV (DMH +5-Florouracil) and GV (essential oil). The histological techniques used were methylene blue, hematoxylin-eosin (HE) dyeing, and immunohistochemistry (IHQ).
RESULTS
The major essential oil compounds were citral (17.25%), δ-citral (10.25%), camphene (9.55%), α-zingiberene (7.57%), nerol (6.37%) and plelandrene (6.83%). For the presence of AC or ACF, we did not observe them in GI and GV, while in GII and GIII, they were observed, in high values, in both regions, but only in the distal region, there was a significant difference between them. For GIV, for both regions, there were significant lower numbers of AC when compared to GIII. As observed, with HE, there were hyperplastic and dysplastic ACF in the proximal and distal portions of the colon. For IHQ analyses, there were positively PCNA antibody marked cells in all experimental groups. Yet, there was no significant correlation of mitotic index among them. Moreover, the results of GIII compared to GIV were very similar.
CONCLUSION
In this sense, the Zingiber officinale essential oil has good antioxidant potential because it presents a mixture of monoterpene and sesquiterpene compounds. Thus, it is able to develop a chemoprotective effect, as it presented similar results to the standard drug, showing cell proliferation control.
Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Antineoplastic Agents; Colorectal Neoplasms; Zingiber officinale; Male; Oils, Volatile; Rats; Rats, Wistar
PubMed: 32711443
DOI: 10.31557/APJCP.2020.21.7.2141 -
The British Journal of Nutrition May 2008Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced...
Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in rats. We have also shown that dietary Ca, antioxidant mix and olive oil inhibit haemin-induced ACF promotion, and normalize faecal lipoperoxides and cytotoxicity. Here we tested if these strategies are effective also against red meat promotion in dimethylhydrazine-induced rats. Three diets with 60 % beef meat were supplemented with calcium phosphate (31 g/kg), antioxidant agents (rutin and butylated hydroxyanisole, 0.05 % each) and olive oil (5 %). ACF, MDF, faecal water cytotoxicity, thiobarbituric acid reactive substances (TBARS) and urinary 1,4-dihydroxynonane mercapturic acid (DHN-MA) were measured. Beef meat diet increased the number of ACF (+30 %) and MDF (+100 %) (P < 0.001), which confirms our previous findings. Promotion was associated with increased faecal water TBARs ( x 4) and cytotoxicity ( x 2), and urinary DHN-MA excretion ( x 15). Ca fully inhibited beef meat-induced ACF and MDF promotion, and normalized faecal TBARS and cytotoxicity, but did not reduce urinary DHN-MA. Unexpectedly, high-calcium control diet-fed rats had more MDF and ACF in the colon than low-Ca control diet-fed rats. Antioxidant mix and olive oil did not normalize beef meat promotion nor biochemical factors. The results confirm that haem causes promotion of colon carcinogenesis by red meat. They suggest that Ca can reduce colorectal cancer risk in meat-eaters. The results support the concept that toxicity associated with the excess of a useful nutrient may be prevented by another nutrient.
Topics: 1,2-Dimethylhydrazine; Acetylcysteine; Animals; Antioxidants; Body Weight; Calcium, Dietary; Cattle; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diet; Eating; Feces; Female; Heme; Meat; Olive Oil; Plant Oils; Rats; Rats, Inbred F344; Thiobarbituric Acid Reactive Substances
PubMed: 17953789
DOI: 10.1017/S0007114507843558 -
The Journal of Biological Chemistry Jun 2010Aging and DNA polymerase beta deficiency (beta-pol(+/-)) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load...
Aging and DNA polymerase beta deficiency (beta-pol(+/-)) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in beta-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in beta-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in beta-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD beta-pol haploinsufficient mice.
Topics: 1,2-Dimethylhydrazine; Animal Feed; Animals; Apoptosis; Colonic Neoplasms; DNA Damage; DNA Polymerase beta; DNA Repair; Folic Acid Deficiency; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Vitamins
PubMed: 20404327
DOI: 10.1074/jbc.M109.069807 -
Journal of Pharmacological Sciences Jan 2021The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the...
Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.
The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue β-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.
Topics: Animals; Anti-Inflammatory Agents; Antidepressive Agents; Antioxidants; Apoptosis; Catechin; Cell Proliferation; Chemoprevention; Colon; Colonic Neoplasms; Dimethylhydrazines; Fluoxetine; Kaempferols; Male; Phytotherapy; Rats, Sprague-Dawley; Rats
PubMed: 33357777
DOI: 10.1016/j.jphs.2020.10.005 -
Biomedicine & Pharmacotherapy =... Oct 2021Callistemon citrinus has terpenes effective in inducing antioxidant enzymes, an important mechanism involved in cancer chemoprevention. This study investigated the...
Callistemon citrinus has terpenes effective in inducing antioxidant enzymes, an important mechanism involved in cancer chemoprevention. This study investigated the chemopreventive efficacy of herbal preparation of C. citrinus leaves against the oxidative stress produced during the colorectal cancer (CRC) in male Wistar rats. The amelioration of toxicity in a model of CRC induced with 1,2-dimethylhydrazine (DMH) was determined by assessing antioxidant enzymes, phase II enzymes activities and lipid peroxidation (LPO) products after 22 weeks of treatment. C. citrinus was administered at a daily oral dose of 250 mg/kg. The activities in proximal, middle and distal colon, liver, kidney and heart were determined. C. citrinus showed a strong antioxidant activity that correlated with the high content of phenolics and terpenoids. DMH treated animals showed a decrease of the enzymes activity in most tissues and the level of reduced glutathione (GSH). Conversely, the levels of lipid peroxidation products were increased. Macroscopic examination revealed the protective effect of C. citrinus in damaged organs caused by DMH. Moreover, histopathological examination of the liver displayed normal structure in the C. citrinus-treated group, unlike the DMH-treated group. C. citrinus supplementation significantly maintained or increased the antioxidant enzyme activities, whereas lipid peroxidation products levels were reduced to values similar to the level of control group. The ability of C. citrinus to induce the antioxidant system reduced the damage of oxidative stress, which makes this plant a good candidate to be used as a prevention agent in treatment of diseases such as colorectal cancer.
Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Antioxidants; Colonic Neoplasms; Lipid Peroxidation; Male; Myrtaceae; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar
PubMed: 34435594
DOI: 10.1016/j.biopha.2021.112070 -
Revista Espanola de Enfermedades... Sep 2005An overexpression of cyclooxygenase-2 (COX-2) has been seen in colon tumors; therefore, COX-2 specific inhibitors may be used as preventive agents. The aim of this study...
BACKGROUND
An overexpression of cyclooxygenase-2 (COX-2) has been seen in colon tumors; therefore, COX-2 specific inhibitors may be used as preventive agents. The aim of this study was to investigate the effect of both selective and non-selective COX-2 inhibitors on the incidence of colonic tumors in a model of chemical carcinogenesis in the rat.
DESIGN
Experimental study with 65 male Sprague-Dawley rats randomly assigned to one of four groups: (a) control (n = 20), with chemical carcinogenesis using 1-2 dimethylhydrazine (1-2 DMH); (b) acetylsalicylic acid (ASA) (n = 15), with chemical carcinogenesis and the addition of ASA at 30 mg/kg; (c) low-dose rofecoxib (n = 15), with chemical carcinogenesis and the addition of rofecoxib at a dose of 1.2 mg/kg; (d) high-dose rofecoxib (n = 15), with carcinogenesis and the addition of rofecoxib at 3 mg/kg. Carcinogenic induction was performed with 1-2 DMH at a weekly dose of 25 mg/kg for 18 weeks. The main parameter evaluated was percentage of neoplastic colonic tissue, which relates tumor surface area to colon surface area.
RESULTS
Rofecoxib at a dose of 3 mg/kg significantly reduced chemical colon carcinogenesis in rats (p < 0.01). Rofecoxib in lower doses had the same effect on adenomas (p < 0.05) with no effect on adenocarcinomas. Rofecoxib reduced COX-2 expression in tumoral tissue from adenomas and adenocarcinomas (p < 0.01).
CONCLUSIONS
Rofecoxib prevents chemical colon carcinogenesis in the rat, with a reduction of tumoral colonic percentage in adenocarcinomas and tumoral COX-2 expression.
Topics: 1,2-Dimethylhydrazine; Animals; Aspirin; Colonic Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Lactones; Male; Rats; Rats, Sprague-Dawley; Sulfones
PubMed: 16266236
DOI: 10.4321/s1130-01082005000900004 -
Food and Chemical Toxicology : An... Aug 2021Since dietary factors are thought to be responsible for high colon cancer risk, we investigated the chemopreventive effect of jabuticaba seed extract (LJE) by...
Ellagitannins from jabuticaba (Myrciaria jaboticaba) seeds attenuated inflammation, oxidative stress, aberrant crypt foci, and modulated gut microbiota in rats with 1,2 dimethyl hydrazine-induced colon carcinogenesis.
Since dietary factors are thought to be responsible for high colon cancer risk, we investigated the chemopreventive effect of jabuticaba seed extract (LJE) by administering yogurt with or without LJE against 1,2 dimethyl hydrazine (DMH)-induced colon carcinogenesis in rats. Results showed that LJE contained a total phenolic content of 57.16 g/100 g of seed extract in which 7.67 and 10.09 g/100 g represented total flavonoids and ellagitannins, respectively. LJE protected DNA and human LDL against induced in vitro oxidation, which was associated with the ellagitannin content and with the free-radical scavenging and reducing capacities. LJE alone had a non-clastogenicity/aneugenicity property, but in combination with cisplatin, it enhanced the chromosome aberrations in cancer cells. In colon cancer-induced rats, yogurt with or without LJE caused a reduction in pro-inflammatory parameters, decreased the RNA expression of antiapoptotic cytokines and increased the expression of proapoptotic cytokines. Moreover, LJE attenuated colon cancer initiation and progression by decreasing aberrant crypt foci and LJE recovered the gut microbiome. Together, this evidence suggests that LJE provides chemopreventive protection against colon cancer development by reducing inflammation and increasing proapoptotic pathways.
Topics: 1,2-Dimethylhydrazine; Animals; Carcinogens; Chromosome Aberrations; Colonic Neoplasms; Gastrointestinal Microbiome; Hydrolyzable Tannins; Inflammation; Male; Mutagenicity Tests; Myrtaceae; Oxidative Stress; Plant Extracts; Precancerous Conditions; Rats; Rats, Wistar; Seeds
PubMed: 34058233
DOI: 10.1016/j.fct.2021.112287 -
Scientific Reports Sep 2022Ficus dubia latex is recognized as a remedy in Asian traditional medicine with various therapeutic effects. The present study aimed to determine the preventive action of...
Ficus dubia latex extract prevent DMH-induced rat early colorectal carcinogenesis through the regulation of xenobiotic metabolism, inflammation, cell proliferation and apoptosis.
Ficus dubia latex is recognized as a remedy in Asian traditional medicine with various therapeutic effects. The present study aimed to determine the preventive action of Ficus dubia latex extract (FDLE) on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis and its mechanisms. The experiment included an initiation model in which rats were orally administered with FDLE daily for 1 week before DMH injection until the end of the experiment, while only after DMH injection until the end in the post-initiation model. The results firstly indicated that FDLE treatment could reduce the level of methylazoxymethanol (MAM) in rat colonic lumen by inhibition of the activities of both phase I xenobiotic metabolizing enzymes in the liver and β-glucuronidase in the colon, leading to reduced DNA methylation in colonic mucosal cells, related to the number of ACF in the initiation stage. Besides, FDLE modulated the inflammation which could suppress the growth and induce apoptosis of aberrant colonic mucosal cells, leading to retardation of ACF multiplicity. Therefore, FDLE showed the ability to suppress the DMH-induced rat ACF formation and inflammation promoted growth of ACF. In conclusion, FDLE had the potential to prevent carcinogens-induced rat colorectal carcinogenesis in the initiation stage.
Topics: Animals; Rats; 1,2-Dimethylhydrazine; Apoptosis; Carcinogenesis; Cell Proliferation; Colonic Neoplasms; Dimethylhydrazines; Ficus; Inflammation; Latex; Plant Extracts; Rats, Wistar; Xenobiotics
PubMed: 36104433
DOI: 10.1038/s41598-022-19843-9