Oncotarget

Research Papers:

Anticancer activity of 2′-hydroxyflavanone towards lung cancer

Sanjay Awasthi _, Sharad S. Singhal, Jyotsana Singhal, Lokesh Nagaprashantha, Hongzhi Li, Yate-Ching Yuan, Zheng Liu, David Berz, Henry Igid, William C. Green, Lukman Tijani, Vijay Tonk, Aditya Rajan, Yogesh Awasthi and Sharda P. Singh

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Oncotarget. 2018; 9:36202-36219. https://doi.org/10.18632/oncotarget.26329

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Abstract

Sanjay Awasthi1, Sharad S. Singhal2, Jyotsana Singhal2, Lokesh Nagaprashantha2, Hongzhi Li3, Yate-Ching Yuan3, Zheng Liu3, David Berz4, Henry Igid1, William C. Green1, Lukman Tijani1, Vijay Tonk5, Aditya Rajan1, Yogesh Awasthi6 and Sharda P. Singh1

1Division of Hematology and Oncology, Department of Internal Medicine, Texas Tech Health Sciences Center, Lubbock, TX 79430, USA

2Department of Medical Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA

3Bioinformatics Core Facility, City of Hope National Medical Center, Duarte, CA 91010, USA

4Beverly Hills Cancer Center, Los Angeles, CA 90211, USA

5Department of Pediatrics, Texas Tech Health Sciences Center, Lubbock, TX 79430, USA

6Department of Biochemistry and Molecular Biology, the University of Texas Medical Branch, Galveston, TX 77555, USA

Correspondence to:

Sanjay Awasthi, email: sanjay.awasthi@ttuhsc.edu

Keywords: 2’-hydroxyflavanone; lung cancer; small cell lung cancer; non-small cell lung cancer; Ralbp1

Received: October 12, 2017     Accepted: October 21, 2018     Published: November 16, 2018

ABSTRACT

In previous studies, we found that 2’-hydroxyflavonone (2HF), a citrus flavonoid, inhibits the growth of renal cell carcinoma in a VHL-dependent manner. This was associated with the inhibition of glutathione S-transferases (GSTs), the first step enzyme of the mercapturic acid pathway that catalyzes formation of glutathione-electrophile conjugates (GS-E). We studied 2HF in small cell (SCLC) and non-small cell (NSCLC) lung cancer cell lines for sensitivity to 2HF antineoplastic activity and to determine the role of the GS-E transporter Rlip (Ral-interacting protein; RLIP76; RALBP1) in the mechanism of action of 2HF. Our results show that 2HF induced apoptosis in both histological types of lung cancer and inhibited proliferation and growth through suppression of CDK4, CCNB1, PIK3CA, AKT and RPS6KB1 (P70S6K) signaling. Increased E-cadherin and reduced fibronectin and vimentin indicated inhibition of epithelial-mesenchymal transition. Additionally, 2HF inhibited efflux of doxorubicin and increased its accumulation in the cells, but did not add to the transport inhibitory effect of anti-Rlip antibodies alone. Binding of Rlip to 2HF was evident from successful purification of Rlip by 2HF affinity chromatography. Consistent with increased drug accumulation, combined treatment with 1-chloro-2, 4-dinitrobenzene, reduced the GI50 of 2HF by an order of magnitude. Results of in-vivo nude mouse xenograft studies of SCLC and NSCLC, which showed that orally administered 2HF inhibited growth of both histological types of lung cancer, confirmed in-vitro study results. Our result suggest that Rlip inhibition is likely a mechanism of action. Our findings are basis of proposing 2HF as therapeutic or preventative drug for lung cancer.


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