Titto A Augustine

Silymarin downregulates COX-2 expression and attenuates hyperlipidemia during NDEA-induced rat hepatocellular carcinoma

Silymarin is a naturally available bioflavonoid and is a strong antioxidant with a capacity to inhibit the formation of tumors in several cancer models. In the present study, we investigated whether dietary supplementation of silymarin has any role in lipid components, lipid-metabolizing enzymes, free fatty acid profile, and expression of cyclooxygenase-2 (COX-2) in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in rats. NDEA-induced rats showed severe hyperlipidemia along with upregulated expression of COX-2 as revealed by western blotting and immunohistochemistry. Dietary silymarin supplementation attenuated this hyperlipidemia and downregulated the expression of COX-2. Thus we conclude that compounds like silymarin with potent hypolipidemic effect are strong candidates as chemopreventive agents for the treatment of liver cancer.

Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer

Background:Telomeres are TTAGGG tandem repeats capping chromosomal ends and partially controlled by the telomerase enzyme. The EGFR pathway putatively regulates telomerase function, prompting an investigation of telomere length (TL) and its association with anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC).Methods:Colorectal cancer cell lines were treated with multiple drugs and sensitivity determined. Clinical information was gathered from 75 patients who had received anti-EGFR drugs. Telomere length was measured using a validated qRT–PCR technique.Results:In CRC cell lines, TL independently predicted cetuximab sensitivity. Cells with shorter TL had growth inhibition of 18.6±3.41% as compared with 41.39±8.58% in longer TL (P=0.02). These in vitro findings were validated clinically, in a robust multivariate model. Among patients with KRas WT tumours, those with longer TL had a superior median progression-free survival (PFS) of 24.9 weeks than those with shorter TL; median 11.1 weeks, HR 0.31; P=0.048.Conclusion:Telomere length could be a potential unique biomarker predictive of clinical benefit (PFS) of mCRC patients treated with anti-EGFR therapy. This is the novel demonstration of a complex hitherto undescribed interaction, placing anti-EGFR therapy, EGFR pathway, and the telomerase complex within a clinical context.

Potent antitumor and antineoplastic efficacy of baicalein on benzo(a)pyrene-induced experimental pulmonary tumorigenesis.

Current study aims to evaluate the efficacy of baicalein (BE), a naturally occurring bioactive flavanoid (5,6,7‐trihydroxy‐flavone), at a dose of 12 mg/kg body wt in Swiss albino mice exposed to tobacco‐specific carcinogen benzo(a)pyrene [B(a)P] (50 mg/kg body wt) for its ability to mitigate pulmonary adenoma formation and growth. Under coarse observation, B(a)P‐administered mice, after 16 weeks, developed macroscopically detectable tumors, whereas oral treatment with BE to the lung cancer–induced mice significantly reduced tumor incidence in 16‐week pre‐ and posttreated groups. A detailed histopathological examination of lung was conducted to determine the degree of cancer progression. Incidence of anaplasia, hyperplasia, dysplasia, severe dysplasia, and adenocarcinoma were evident in carcinogen‐administrated group in 6, 10, 12, 14, and 16th weeks, respectively, whereas these anomalies were effectively reduced after pre‐ and posttreatment with BE. In the pretreatment group, BE significantly arrested tumor multiplicity by approximately 65% and tumor load by approximately 88%, while in the posttreatment, the compound significantly reduced the tumor multiplicity by approximately 48% and tumor load by approximately 61%. Further analysis of serum tumor markers like carcinoembryonic antigen, CK 19 fragments (CYFRA 21‐1), and tissue marker enzymes like aryl hydrocarbon hydroxylase, adenosine deaminase, γ‐glutamyl transpeptidase, 5′‐nucleotidase, and lactate dehydrogenase in serum and lung homogenate was carried out to substantiate the anticarcinogenic effect of BE. The overall data from our experiments suggested that BE significantly inhibited pulmonary adenoma formation and growth, thus revealing its potent antitumorigenic effect.

Toll-like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer

New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene (40-45% of all patients). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a double stranded (ds) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors. Toll Like Receptor (TLR) 3, a member of the toll like receptor family of the host innate immune system is the pattern recognition motif for dsRNA pathogens. Using TLR3 expressing commercial HEK-Blue™-hTLR3 cells we confirm that TLR3 is the host pattern recognition motif responsible for the detection of reovirus. Further, our investigation with KRAS mutated HCT116 cell line showed that effective expression of host TLR3 dampens the infection potential of reovirus by mounting a robust innate immune response. Down regulation of TLR3 expression with siRNA improves the anticancer activity of reovirus. In vivo experiments using human CRC cells derived xenografts in athymic mice further demonstrate the beneficial effects of TLR3 knock down by improving tumor response rates to reovirus. Strategies to mitigate the TLR3 response pathway can be utilized as a tool towards improved reovirus efficacy to specifically target the dissemination of KRAS mutated CRC.

Telomere length regulation through epidermal growth factor receptor signaling in cancer

Length of the telomere (TL), a structure at the tip of chromosome that protects and ensures stability, is determined by multi-protein complexes such as telosome/shelterin and telomerase. Earlier studies from our laboratory show that longer TL has potential to be positive predictive biomarker of clinical outcome to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in patients with KRAS WT metastatic colorectal cancer. Although there is extensive literature suggesting the role of shelterin and telomerase, not much literature exists that describes the role of EGFR and KRAS pathway in regulating TL. This detailed review focuses on an insight into various components, including proteins, enzymes and transcription factors, interlinking between EGFR pathways and telomerase that regulate TL.

A single nucleotide polymorphism in the MGMT gene is a novel prognostic biomarker in patients with metastatic colorectal cancer.

Background: Discovery of novel biomarkers of prognosis and drug response remains an elusive, yet critical goal. Thus, accurate and rapid screening of an array of pertinent mutations/SNPs is an essential step in cancer management. Methods: Using a high-throughput multiplex PCR microarray technique, we simultaneously screened the mutational status/SNP of 32 hotspots in multiple genes for metastatic colorectal cancer (mCRC) from 126 formalin fixed paraffin embedded samples from 78 patients. The efficacy of the technology was validated by cross-comparison with conventional Sanger sequencing and Original Research Article