Virtual Library
Start Your Search
S. Awasthi
Author of
-
+
P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.04-064 - 2'-Hydroxyflavanone Inhibits Lung Cancer Growth by Inhibiting Tumor Cell Proliferation and Angiogenesis (ID 3141)
09:30 - 09:30 | Author(s): S. Awasthi
- Abstract
Background:
Epidemiologic studies suggest that citrus fruit consumption reduces cancer risk. We have previously shown that 2-hydroxyflavanone (2HF), a naturally occurring compound in citrus fruits, exerts antineoplastic effects in-vitro and in-vivo against renal cell carcinoma in a manner dependent on VHL function and expression of glutathione S-transferase p (GSTP). GSTP is a stress- and xenobiotic-defense protein that catalyzes the first step committed step of the mercapturic acid pathway (MPy).
Methods:
We performed mining of molecular databases, including the TCGA. Then, we conducted cytotoxicity assays, followed by signaling studies. Finally xenograft experiments, using nu/nu athymic nude mice were performed.
Results:
2HF inhibited non-small and small cell lung cancer cell line growth in-vitro. Reduced CDK4 and cyclin B1 levels were correlated with G~2~/M arrest. Apoptosis was accompanied by Bcl2 down-regulation and Bax upregulation. Inhibition of PI3K signaling was evident from reduction in AKT and p70S6K phosphorylation. Reduction of vimentin and fibronectin and increase in E-cadherin indicated inhibition of epithelial-mesenchymal transition. Remarkably, 2HF reduced the expression of RLIP76/RALBP1, a rate-limiting glutathione-conjugate/multidrug transporter of the MPy. 2HF also inhibited the transport activity of RLIP76. Dose-dependent 2HF cytotoxicity was enhanced by antibodies to RLIP76. Oral dosing of 2HF resulted in 3-5 mM serum concentrations and inhibited the growth of H1618 and H358 NSCLC cell line xenografts in nu/nu athymic nude mice. Residual tumors had reduced Ki67 and CD31 staining, indicating inhibited proliferation and angiogenesis. Higher MPy expression in lung cancer was evident from increased RLIP expression in human lung cancer tissues, and analyses of the TCGA database showed that RLIP76 expression was inversely correlated with survival in lung adenocarcinoma.
Conclusion:
Taken together, these studies demonstrate antineoplastic activity of 2HF against lung cancer cell lines in-vitro and in-vivo through a novel mechanism that simultaneously causes down-regulation of MaP, stress-signaling, EMT and angiogenesis. Excellent oral absorption of 2HF indicates its suitability for therapy and possibly prevention of lung cancer.
