Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers. Several mechanisms may be involved in dysregulation of this pathway. They include p53 mutation, a mutation in HMG-CoAR and sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP as its regulator, PKB/Akt activation, decreased AMPK activation, and activation of transcription factors such as: SREBP and HIF-1. Statins as inhibitors of MVA pathway might be useful for cancer prevention and/or treatment through their interactions with essential cellular functions, such as cell proliferation and differentiation. Other inhibitors are also designed for inhibition of this key pathway and their mechanism of action was investigated. In the present review, we will first describe about some inhibitors of MVA, including statins that have been suggested for cancer treatment. We will then discuss about the mechanisms involved in MVA dysregulation, especially in cancer.
We previously showed the anticancer effect of crocin, a saffron carotenoid, in both breast and gastric cancers in animal models, but its mechanism of action is not clearly known, yet. In this study, the effect of crocin on cell cycle regulators is investigated. Female Wistar Albino rats were divided into two groups, with or without N-nitroso-N-methylurea (NMU) injection. After tumor formation, each group of rats was divided into two subgroups, receiving crocin or vehicle only. After 5 weeks, the rats were sacrificed and the tumors were retained for pathologic investigation and determination of the parameters. Before crocin treatment, the tumor volumes were 13.27±3.77 and 12.37±1.88, but at the end of the experiment, they were 23.66±8.82 and 11.91±2.27 in the control and crocin-treated groups, respectively. Pathologic investigation indicated the adenocarcinoma induction by NMU. Reverse transcription-polymerase chain reaction and Western blot analysis showed overexpression of cyclin D1 and p21(Cip1) in the NMU-induced breast tumors; however, the expression of both of them suppressed by crocin treatment. The previous studies indicated that crocin induces apoptosis in tumor tissue. In this study, we show that it also suppresses tumor growth and induces cell cycle arrest by downregulation of cyclin D1. In addition, crocin suppressed p21(Cip1) in a p53-dependent manner.
This experiment was conducted to determine the effects of the diet physical form, Mash (M), Pellet (P) and Extruded (E) on the growth performance, carcass characteristics and metabolic disorders ascites (AS) and as well as sudden death syndrome (SDS) in the broiler chickens. In this respect, feed intake (FI), weight gain (WG) and mortalitywere recorded throughout the experiment and biochemical parameters, hematology and carcass characteristics were tested at 35 and 42 days of age respectively. The results showed that with the increase of the average daily weight gain (ADWG) (p<0.01), the relative breast weight to the carcass weight (p<0.05), better feed conversion ratio (p<0.01), the lower relative cecum weight and gizzard to the carcass weight (p<0.05) were observed by applying the E diet form, as compared with the other treatments. A significant increase in the average daily feed intake (ADFI) was also observed by using the P diet form (p<0.01). Hematological parameters including hemoglobin (Hb), hematocrit (HCT), urea, uric acid, triglyceride, the ratio of low-density lipoprotein to high-density lipoprotein (LDL/HDL), very low-density lipoprotein (VLDL), enzyme activities of aspartate aminotransferase(AST) and alanine aminotransferase (ALT) of the blood serum were lowered by applying the M treatment, as compared with the other treatments (p<0.05). The results indicated that the performance and carcass characteristics were improved by the E and P diet forms; also, with raising the hematology parameters in these treatments, the mortality of ascites and SDS was increased.
Background: Acute lymphoblastic leukemia (ALL) is classified as a malignant disorder. L-asparaginase has several adverse effects and low serum stability as a chemotherapy agent for ALL treatment. Our previous study demonstrated an improvement in the biochemical properties of chemically modified L-asparaginase with carboxymethyl dextran. Afterwards, this study was conducted to confirm the potential application of these findings in the NALM-6 cell line. Methods and Results: In this experimental study, the MTT assay was used to determine the effect of modified L-asparaginase, on the viability of the NALM-6 cell line. Flow cytometry and real-time RT-PCR techniques were employed to assess cell apoptosis and changes in the expression of the ATG2B and LC3-II genes. After 48 hours of treatment, conjugated L-asparaginase decreased the viability of the NALM-6 cell line, more than those of native L-asparaginase (P=0.01). Flow cytometry analysis revealed that modified L-asparaginase, increasesapoptosis compared to the control sample at all times (after 24 hours P<0.01, 48 hours P<0.01 and 72 hours P=0.03). This increase was more than which, the native enzyme caused. Additionally, quantitative RT-PCR analysis revealed that both enzymes increased LC3-II gene expression after 24 hours (P<0.01) while the native enzyme caused the increase more than the modified one (P=0.02). A significant increase in ATG2B expression was observed only after 24 hours of treatment with the native enzyme (P<0.01). Conclusions: This chemical modification induces apoptosis more, and stimulates the autophagy less than the native enzyme, and leads the cells to death instead of resistance to treatment.
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