Anticancer activity of 2'-hydroxyflavanone towards lung cancer.

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

doi:10.18632/oncotarget.26329

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.

Highlights

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide, the most common cancer diagnosed in men with more than 1.5 million persons annually [1, 2]
Clonogenic assays confirmed that 2HF inhibited lung cancer cell survival as shown for the H358 and H520 non-small cell lung cancer (NSCLC) cell lines (54 and 46% inhibition, respectively, p < 0.001)
2HF inhibited the growth of ALK generearranged H3122 and H2228 adenocarcinoma NSCLC cell lines

Summary

Introduction

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide, the most common cancer diagnosed in men with more than 1.5 million persons annually [1, 2] These numbers are a stark reminder of the inadequacy of present preventative and therapeutic interventions for this disease epidemic. Because TP53 normally activates apoptosis of cells with irreparable genotoxic injury, its loss allows the survival of genetically damaged cells As these damaged cells accumulate, they develop increasing genetic instability that accelerates carcinogenesis [13, 14]. Though genoprotective xenobiotic defenses exert beneficial effects by reducing exposure to genotoxins on normal or premalignant cells, their anti-apoptotic activity permits survival and accumulation of pre-malignant cells that harbor increasing numbers of cancer promoting DNA lesions. The cancer-protective effects of xenobiotic defenses become cancer promoting since their anti-apoptotic activities promote survival of cancer stem cells and mediate drug-resistance through antiapoptotic, drug-metabolism, and drug-efflux processes

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