Momordicine-I, a Bitter Melon Bioactive Metabolite, Displays Anti-Tumor Activity in Head and Neck Cancer Involving c-Met and Downstream Signaling.

Subhayan Sur,Ratna B Ray,Mostafa E Rateb,T Scott Isbell,Kalyan Nagulapalli Venkata,Robert Steele

doi:10.3390/cancers13061432

Abstract

Simple SummaryThe incidence of head and neck cancer (HNC), one of the most aggressive cancers, is increasing rapidly globally. Conventional and targeted therapies show limited success with several undesirable side effects. Thus, there is a critical clinical need to identify additional alternative therapeutic strategies for successfully managing the disease. Preclinical and clinical studies indicate the crucial roles of dietary phytochemicals to manage different cancers. We and others previously showed the potential anticancer effect of bitter melon extract (BME) to prevent various cancers, including HNC. In this study, we identified momordicine-I (M-I) as a bioactive component in the BME. Subsequent mechanistic study showed that M-I inhibited HNC cell (JHU022, JHU029, Cal27) proliferation involving c-Met and downstream signaling. In pre-clinical mouse models, M-I showed similar effectiveness to prevent HNC tumor growth in mice with no apparent toxic side effect, suggesting an additional option for HNC therapy.Head and neck cancer (HNC) is one of the most aggressive cancers, and treatments are quite challenging due to the difficulty in early diagnosis, lack of effective chemotherapeutic drugs, adverse side effects and therapy resistance. We identified momordicine-I (M-I), a bioactive secondary metabolite in bitter melon (Momordica charantia), by performing liquid chromatography-high resolution electrospray ionization mass spectrometry (LC-HRESIMS) analysis. M-I inhibited human HNC cell (JHU022, JHU029, Cal27) viability in a dose-dependent manner without an apparent toxic effect on normal oral keratinocytes. Mechanistic studies showed that M-I inhibited c-Met and its downstream signaling molecules c-Myc, survivin, and cyclin D1 through the inactivation of STAT3 in HNC cells. We further observed that M-I was non-toxic and stable in mouse (male C57Bl/6) blood, and a favorable pharmacokinetics profile was observed after IP administration. M-I treatment reduced HNC xenograft tumor growth in nude mice and inhibited c-Met and downstream signaling. Thus, M-I has potential therapeutic implications against HNC.

Highlights

Head and neck cancer (HNC) arises from the mucosal surfaces of the oral cavity, oropharynx, larynx, paranasal sinuses, nasal cavity, and salivary glands, and is considered the sixth most common cancer worldwide [1]
FFigiguurree11. .MMaasss--ssppeeccttrroommeettrriiccaannaallyyssiissooffbbititteerrmmeelolonneexxttrraaccttaannddidideennttifiifcicaattiioonnooffmmoommoorrddicicininee--II..((AA))LLCCtrtraacceeooffbbititeterr mmeelolonneexxtrtaractctddoonneebybyHHRRMMS.ST. hTehererdedararrorwowinidnidcaicteadtetdhethperpesrensecne coef omfommoomrdoircdinicei-nIe(-MI (-MI) p-Ie)apke.a(kB.)(CBh) eCmheicmalicsatrlusctrturcetuorfe momordicine-I. (C) HNC cells (Cal27, JHU029, JHU022) and control normal oral keratinocytes (NOK) were treated with M-I at different concentration for 48 h, and cytotoxicity assay was performed
Our results suggested that M1 inhibits c-Met signaling in the prevention of HNC growth (Figure 4)

Summary

Introduction

Head and neck cancer (HNC) arises from the mucosal surfaces of the oral cavity, oropharynx, larynx, paranasal sinuses, nasal cavity, and salivary glands, and is considered the sixth most common cancer worldwide [1]. The epidermal growth factor receptor (EGFR) inhibitors are the only approved drugs for targeted therapy with limited success and resistance [3,4]. Compensatory activation of another receptor kinase mesenchymal-epithelial transition factor (c-Met) potentially reduces the efficacy of anti-EGFR inhibitors [3]. The c-Met signaling shares common down-stream targets with EGFR and induces HNC cell proliferation, migration, invasion, and metastasis. Clinical studies using c-Met inhibitors and monoclonal antibodies are in developing stages. Programmed cell death receptor (PD-1) monoclonal antibodies nivolumab and pembrolizumab were approved in 2016 to treat the advanced and therapy resistance cases [3,4]. The development of additional therapeutic strategies is necessary for successfully managing the disease

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