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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/β-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.

Polygonum species are used in traditional medicine in many countries; some are also consumed as vegetables in Turkey. The ethanolic, methanolic, and chloroform extracts of four Polygonum species growing in Istanbul, namely P. aviculare, P. patulum subsp. pulchellum, P. lapathifolium, and the only endemic species P. istanbulicum were evaluated for their antioxidant, anti-acetylcholinesterase (AChE), and anticancer potentials. The total phenolic and flavonoid contents of the extracts were determined by Folin-Ciocalteu and aluminium chloride methods, respectively. The antioxidant capacities of the extracts were determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric-reducing antioxidant power (FRAP) assays. The AChE inhibitory activities of the extracts were determined using the Ellman method. Each extract was screened for cytotoxic activity against NRK-52E and HeLa cervical cancer cell lines using the MTT assay. Among the extracts screened, ethanolic extract of P. istanbulicum showed the highest total phenolic (207.03 ± 14.12 mg GAE/g extract) and total flavonoid (124.95 ± 7.84 mg CE/g extract) contents, and antioxidant activity (DPPH EC50, 8.09 ± 0.50 mg/mL). The chloroform extract of P. lapathifolium exhibited the lowest total phenolic (22.33 ± 3.05 mg GAE/g extract) and total flavonoid (11.66 ± 0.36 mg CE/g extract) contents, and antioxidant activity (DPPH EC50, 218.44 ± 24.46 mg/mL). The extracts exhibited AChE inhibitory activity in a dose-dependent manner, particularly the ethanolic extract of P. istanbulicum which displayed strongest inhibition against AChE (88.2 ± 3.44%). AChE inhibition was minimal (32.19 ± 2.09 to 48.34 ± 3.41%) in the chloroform extracts. All ethanolic extracts revealed cytotoxic activity toward HeLa cells, while they were not cytotoxic toward NRK-52E cells. The ethanolic extract of P. lapathifolium showed the most potent cytotoxicity against HeLa cells (IC50, 8.70 ± 1.35 µg/mL). Results suggested that ethanol was the best solvent for extracting the phenolic, antioxidant, and anti-AChE compounds, and P. istanbulicum may be a potential source of these compounds. Further investigations are nevertheless required to identify the bioactive compounds present in Polygonum species.