Novel Cytotoxic Sesquiterpene Ester Derivatives from the Roots of Ferula mervynii.

This study is the first chemical investigation of Ferula mervynii M. Sagiroglu & H. Duman, an endemic species to Eastern Anatolia. The isolations of nine compounds including six previously undescribed sesquiterpene esters, 8-trans-cinnamoyltovarol (1), 8-trans-cinnamoylantakyatriol (3), 6-acetyl-8-trans-cinnamoyl-3-epi-antakyatriol (5), 6-acetyl-8-trans-cinnamoylshiromodiol (6), 6-acetyl-8-trans-cinnamoylfermedurone (7), and 6-acetyl-8-trans-cinnamoyl-(1S),2-epoxyfermedurone (8), were described along with three known sesquiterpene esters, 6-acetyl-8-benzoyltovarol (2), 6-acetyl-8-trans-cinnamoylantakyatriol (4), and ferutinin (9). The structures of novel compounds were elucidated through extensive spectroscopic analyses and quantum chemistry calculations. The putative biosynthetic pathways for compounds 7 and 8 were discussed. The extracts and isolated compounds were tested for cytotoxic activity against the COLO 205, K-562, MCF-7 cancer cell lines, and Human Umbilical Vein Endothelial Cell (HUVEC) lines using MTT assay. Compound 4 showed the highest activity against the MCF-7 cell lines with an IC50 value of 16.74±0.21 µM.

Sesquiterpene Coumarins, Chromones, and Acetophenone Derivatives with Selective Cytotoxicities from the Roots of Ferula caspica M. Bieb. (Apiaceae).

In search of selective cytotoxic compounds from Ferula species as potential leads for the treatment of various cancer diseases, a bioactivity-guided isolation study was performed on the roots of Ferula caspica M. Bieb. COLO 205 (colon), K-562 (leukemia), and MCF-7 (breast) cancer cell lines were used to monitor the cytotoxic activity of column fractions and determine the IC50 value of the active compounds. In addition to the seven known (5-11) compounds, four previously unknown compounds: kayserin A (1), kayserin B (2), 8'-epi-kayserin B angelate (3), and 3-epi-ferulin D (4) were isolated from the dichloromethane extract of the roots of F. caspica. Structure elucidation of the isolated compounds was carried out by extensive spectroscopic analyses such as 1D- and 2D-NMR spectroscopy, High-Resolution Mass Spectroscopy (HRMS), IR spectroscopy, and UV spectroscopy. Although all of the isolated compounds showed various degrees of cytotoxic activity on COLO 205, K-562, and MCF-7 cancer cell lines, the most potent compounds were identified in the following order: 1-Hydroxy-1-(1'-farnesyl)-4,6-dihydroxyacetophenone (HFDHAP, 11), 3-epi-ferulin D (3EFD, 4), and 7-desmethylferulin D (7DMFD, 6). The cytotoxic activities of all three compounds were more potent than that of the reference compound cisplatin (Cis) against all tested cancer cell lines. Still, only HFDHAP (11) was more potent than the reference compound doxorubicin (Dox) against the MCF-7 cancer cell line. The mechanism of action of these three compounds was investigated on the COLO 205 cell line. The results indicated that compounds 4, 6, and 11 trigger caspase-3/8/9 activation and suppress the anti-apoptotic protein, Bcl-xL. Molecular docking studies confirmed the interactions of the three cytotoxic molecules with the active site of the Bcl-xL protein.

Sesquiterpene Coumarin Ethers with Selective Cytotoxic Activities from the Roots of Ferula huber-morathii Pesmen (Apiaceae) and Unequivocal Determination of the Absolute Stereochemistry of Samarcandin.

Ancient physicians frequently used the resin of Ferula species to treat cancer. Today, some folkloric recipes used for cancer treatment also contain the resin of Ferula species. The dichloromethane extract of the roots of Ferula huber-morathii exhibited cytotoxic activities against COLO 205 (colon), K-562 (lymphoblast), and MCF-7 (breast) cancer cell lines (IC50 = 52 µg/mL, 72 µg/mL, and 20 µg/mL, respectively). Fifteen sesquiterpene coumarin ethers with cytotoxic activity were isolated from the dichloromethane extract of the roots of F. huber-morathii using bioactivity-directed isolation studies. Extensive spectroscopic analyses and chemical transformations have elucidated the structures of these sesquiterpene coumarin ethers as conferone (1), conferol (2), feselol (3), badrakemone (4), mogoltadone (5), farnesiferol A (6), farnesiferol A acetate (7), gummosin (8), ferukrin (9), ferukrin acetate (10), deacetylkellerin (11), kellerin (12), samarcandone (13), samarcandin (14), and samarcandin acetate (15). The absolute configuration of samarcandin (14) was unequivocally determined by the X-ray crystallographic analysis of the semi-synthetic (R)-MTPA ester of samarcandin (24). Conferol (2) and mogoltadone (5) were found to be the most potent cytotoxic compounds against all three cancer cell lines; furthermore, these compounds exhibit low cytotoxic activity against the non-cancerous human umbilical vein epithelial cells (HUVEC) cell line. Investigation of the biological activity mechanisms of mogoltadone (5) revealed that while suppressing the levels of Bcl-XL and procaspase-3 in the COLO 205 cancer cell line, it did not have a significant effect on the Bcl-XL, caspase-3, and ß-catenin protein levels of the HUVEC cell line, which may explain the cytotoxic selectivity of mogoltadone (5) on cancer cell lines.

Identification of AKT1/ß-catenin mutations conferring cetuximab and chemotherapeutic drug resistance in colorectal cancer treatment.

In anticancer therapy, the effectiveness of therapeutics is limited by mutations causing drug resistance. KRAS mutations are the only determinant for cetuximab resistance in patients with colorectal cancer (CRC). However, cetuximab treatment has not been fully successful in the majority of patients with wild-type (WT) KRAS. Therefore, it is important to determine new predictive mutations in CRC treatment. In the present study, the association between AKT1/ß-catenin (CTNNB1) mutations with the drug resistance to cetuximab and other chemotherapeutics used in the CRC treatment was investigated by using site-directed mutagenesis, transfection, western blotting and cell proliferation inhibition assay. Cetuximab resistance was higher in the presence of AKT1 E17K, E49K and L52R mutations, as well as CTNNB1 T41A, S45F and S33P mutations compared with that of respective WT proteins. AKT1/CTNNB1 mutations were also associated with oxaliplatin, irinotecan, SN-38 and 5-fluorouracil resistance. Furthermore, mutant cell viability in oxaliplatin treatment was more effectively inhibited compared with that of the other chemotherapeutic drugs. In conclusion, AKT1/CTNNB1 mutations may be used as an important predictive biomarker in CRC treatment.

Antioxidant, Anti-acetylcholinesterase, Anti-inflammatory and DNA Protection Activities of Glaucium grandiflorum var. grandiflorum.

In this study, antioxidant, antiacetylcholinesterase, anti-inflammatory, and DNA protecting activities of the aerial parts of Glaucium grandiflorum var. grandiflorum were evaluated. The lyophilized methanolic extract of the aerial parts of G. grandiflorum var. grandiflorum was investigated for potential in-vitro antioxidant properties in thiobarbituric acid test using the lipid peroxidation of liposomes, ferric ion reducing antioxidant power (FRAP), 1,1-diphenyl-2-picrylhydrazyl,2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonate) free-radicals and hypochlorous acid scavenging assays. The extract demonstrated antioxidant activity in all the assays. The (AChE) inhibition capacity of the lyophilized methanolic extract at 320 µg/mL (80.75 ± 1.59%) was found to be strong and almost equal to the inhibition capacity of the positive control, galantamine (82.23 ± 2.21%) at 25 µg/mL. The significant AChE inhibitory activity suggests that the extract may be beneficial in the treatment of Alzheimer's disease. The extract also showed inhibitory activity against plasmid DNA damage (94%), as well as COX-2 69.05%, which is a target for many anti-inflammatory and cancer-preventive drugs. These results indicate that G. grandiflorum var. grandiflorum methanolic extract is an excellent source of compounds with antioxidant, anti-acetylcholinesterase and anti-inflammatory properties that prevent DNA damage.

Association of Three Single Nucleotide Polymorphisms in MTR and MTRR Genes with Lung Cancer in a Turkish Population.

AIMS: Folate metabolism plays a critical role in DNA methylation and synthesis. Polymorphisms in folate metabolism may affect enzyme activities and thereby affect the cancer risk. Methionine synthase (MTR) and methionine synthase reductase (MTRR) are critical enzymes for the folate cycle. In this study, possible associations between genetic variabilities in MTR and MTRR and susceptibility to lung cancer (LC) were investigated in a Turkish population. METHODS: A case-control study with 193 LC cases and 199 noncancerous controls was conducted. DNA was extracted from leukocytes using the high pure polymerase chain reaction (PCR) template preparation kit. The MTR 2756 A>G (rs1805087), MTRR 524 C > T (rs1532268), and MTRR 66 A>G (rs1801394) genotypes were determined using PCR-restriction fragment length polymorphism (PCR-RFLP) assays. The genotype and haplotype analyses of these polymorphisms were performed using SPSS 21 and Haploview 4.2, respectively. RESULTS: An association between the MTRR A66G polymorphism and LC (p = 0.042) was found. In addition, this allele was observed more frequently in smokers compared to nonsmokers (p = 0.030). In contrast, the distribution of the MTR 2756 A>G and the MTRR 524 C > T allele frequencies were similar in the subject cases and controls. CONCLUSIONS: In conclusion, the present study suggests an association between the MTRR 66 A>G gene polymorphisms and LC risk in a Turkish population.

Paraoxonase-1 192/55 polymorphisms and the risk of lung cancer in a Turkish population.

AIM: The purpose of the present study was to investigate the possible association of paraoxonase-1 (PON1) 192/55 polymorphisms with lung cancer (LC) risk in a Turkish population. MATERIALS AND METHODS: A population-based, case-control study was carried out, including 223 patients with LC and 234 controls. The frequencies of PON1 192/55 genotypes were compared in patient and control groups using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Distribution of PON1 192 R (+) genotype was found to be significantly higher in patients with LC compared to the controls (odds ratio: 1.497, 95% confidence interval: 1.034-2.166). This difference was especially noteworthy in patients with small cell carcinoma and squamous cell carcinoma. CONCLUSION: This is the first case-control study on the association between PON1 polymorphisms and LC susceptibility in a Turkish population. Our results suggest that PON1 192 polymorphsim is associated with an increased risk of LC in the Turkish population and may be a useful genetic marker for small cell and squamous cell carcinoma.