Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds.

James Knockleby,Phuong Mai Le,Hoyun Lee,Thanh Tam Nguyen,Bruno Pradines,Mathieu Gendrot,Joel Mosnier,Thi Thuy Trinh

doi:10.3390/molecules25163755

Abstract

Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine (1) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC50 values ranging from 1.66 to 4.35 μM. Morever, oxostephanine (1) is on average two-fold more active against cancer cells than stephanine (3), having a similar chemical structure. Cells treated with oxostephanine (1) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine (1) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine (1), thailandine (2) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine (2) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure–activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.

Highlights

Aurora kinases are an important class of cell cycle kinases that regulate and coordinate many aspects of mitotic cell division
MB2L-CH fraction was effective on all of the cell lines examined, it did not show any selectivity between four cancer cell lines and two non-cancer cell lines (184B5 and MCF10A)
The MB2L-B fraction was effective against only MDA-MB-468; it is very selective against the cancer cell line when compared with its cytotoxicity against 184B5 (3.2-fold) and MCF10A (7.8-fold) non-cancer cells (Table 1)

Summary

Introduction

Aurora kinases are an important class of cell cycle kinases that regulate and coordinate many aspects of mitotic cell division. Aurora A localizes to the microtubules and centromeres and plays an important role in centrosome function and bipolar spindle assembly [1,2]. Much effort has been made over the last decade and a half to find inhibitors that can target Aurora kinases as they may be effective anticancer therapeutic targets [1,2]. Pfark-1, an Aurora kinase A, is required at the S to M phase transition of the parasite cycle and is highly conserved in human and rodent malaria species and other apicomplexan parasites [5,6]. Hesparadin, a human Aurora B inhibitor, and analogs were identified to be highly potent against P. falciparum [8]

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