Imperatorin as a Promising Chemotherapeutic Agent Against Human Larynx Cancer and Rhabdomyosarcoma Cells.

Aneta Grabarska,Jolanta Smok-Kalwat,Justyna Szumiło,Magdalena Dmoszyńska-Graniczka,Sherief Khalifa,Michał Kiełbus,Ewa Nowosadzka,Adolfo Rivero-Müller,Janusz Klatka,Krystyna Skalicka-Woźniak,Krzysztof Kupisz,Andrzej Stepulak,Paulina Miziak,Krystyna Kowalczuk,Krzysztof Polberg

doi:10.3390/molecules25092046

Abstract

Naturally occurring coumarins are bioactive compounds widely used in Asian traditional medicine. They have been shown to inhibit proliferation, induce apoptosis, and/or enhance the cytotoxicity of currently used drugs against a variety of cancer cell types. The aim of our study was to examine the antiproliferative activity of different linear furanocoumarins on human rhabdomyosarcoma, lung, and larynx cancer cell lines, and dissolve their cellular mechanism of action. The coumarins were isolated from fruits of Angelica archangelica L. or Pastinaca sativa L., and separated using high-performance counter-current chromatography (HPCCC). The identity and purity of isolated compounds were confirmed by HPLC-DAD and NMR analyses. Cell viability and toxicity assessments were performed by means of methylthiazolyldiphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, respectively. Induction of apoptosis and cell cycle progression were measured using flow cytometry analysis. qPCR method was applied to detect changes in gene expression. Linear furanocoumarins in a dose-dependent manner inhibited proliferation of cancer cells with diverse activity regarding compounds and cancer cell type specificity. Imperatorin (IMP) exhibited the most potent growth inhibitory effects against human rhabdomyosarcoma and larynx cancer cell lines owing to inhibition of the cell cycle progression connected with specific changes in gene expression, including CDKN1A. As there are no specific chemotherapy treatments dedicated to laryngeal squamous cell carcinoma and rhabdomyosarcoma, and IMP seems to be non-toxic for normal cells, our results could open a new direction in the search for effective anti-cancer agents.

Highlights

For many years, plants have been important sources of bioactive compounds widely used in medicine [1]
Coumarins and coumarin-related compounds have been under extensive studies and non-small-cell lung cancers (NSCLCs)
We demonstrated that simple coumarin derivatives, including umbelliferone, scoparone, and herniarin, inhibited proliferation and www.mdpi.com/journal/molecules tumors in vivo [24]

Summary

Introduction

Plants have been important sources of bioactive compounds widely used in medicine [1]. One of the largest group of phytochemicals, which possess many potential therapeutic properties, are naturally occurring coumarins. These substances are mainly classified based on their chemical structure into simple coumarins, linear and angular furanocoumarins, and pyranocoumarins [2]. Linear furanocoumarins called psoralens are well known as photosensitizing agents, which have been used in PUVA (psoralens plus UV-A) therapy for the treatment of autoimmune or hyper-proliferative skin diseases such as psoriasis and vitiligo [5]. Furanocoumarin/ultraviolet therapy known as photopheresis has become an effective treatment of cutaneous T-cell lymphoma [6]. Linear furanocoumarins have been described to have antimicrobial, antioxidant, anti-inflammatory, antidiabetic [7], and anticolvulsant [8,9] activities

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Conclusion