Abstract
We previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds. We report the structures of the seven most abundant GLE compounds and their selective efficacy against triple negative (TNBC) and inflammatory breast cancers (IBC) and other human cancer cell types (solid and blood malignancies) to illustrate their potential as anti-cancer agents. Three of the seven compounds (ergosterol, 5,6-dehydroergosterol and ergosterol peroxide) exhibited significant in vitro anti-cancer activities, while we report for the first time the structure elucidation of 5,6-dehydroergosterol from Ganoderma lucidum. We also show for the first time in TNBC/IBC cells that ergosterol peroxide (EP) displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation, and PARP cleavage. EP decreased migratory and invasive effects of cancer cells while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc in the tested IBC cells. Our investigation also indicates that these compounds induce reactive oxygen species, compromising cell fate. Furthermore, we generated a superior derivative, ergosterol peroxide sulfonamide, with improved potency in IBC cells and ample therapeutic index (TI > 10) compared to normal cells. The combined studies indicate that EP from Ganoderma lucidum extract is a promising molecular scaffold for further exploration as an anti-cancer agent.
Highlights
Increased toxic effects from conventional therapies, as well as evidence from recent reports that prove the efficacy of natural therapies, have caused a rise in their use by patients with cancer (Gao et al, 2003; Chen et al, 2006; Jin et al, 2016; Suárez-Arroyo et al, 2017)
We show that ergosterol peroxide (EP) displayed a reduction in cell migration and invasion, and these results are consistent with our previous studies with Ganoderma lucidum extract (GLE) wherein we demonstrated reduced invasion potential of breast cancer cells (MartinezMontemayor et al, 2011; Suarez-Arroyo et al, 2013, 2016; Suárez-Arroyo et al, 2017)
The isolated compounds of GLE, display biological activity across multiple cancer cell lines, with several degrees of potency. This investigation demonstrates for the first time (i) that EP as a single component of GLE, is the most biologically active compound against aggressive inflammatory breast cancer models with promising EC50 values in the low micromolar range and ample therapeutic index in normal cells. (ii) A detailed report of the X-ray crystal of 5,6-dehydroergosterol from Ganoderma lucidum; and (iii) that we developed improved derivatives of GA-01, ergosterol, 5,6-dehydroergosterol and EP by addressing their solubility
Summary
Increased toxic effects from conventional therapies, as well as evidence from recent reports that prove the efficacy of natural therapies, have caused a rise in their use by patients with cancer (Gao et al, 2003; Chen et al, 2006; Jin et al, 2016; Suárez-Arroyo et al, 2017). Among these therapies is the whole medicinal mushroom Ganoderma lucidum, which has been used in traditional Chinese medicine for more than two millennia (Paterson, 2006). The spores contain mainly lanostane-type triterpenes (Xie et al, 2006) and polysaccharides (Huie and Di, 2004) similar to those found in the fruiting body, which are the main chemical compounds to which anti-cancer activities of GLE are attributed
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