3,6-Epidioxy-1,10-bisaboladiene and sulfasalazine synergistically induce ferroptosis-like cell death in human breast cancer cell lines.

3,6-Epidioxy-1,10-bisaboladiene (EDBD) is an endoperoxide compound isolated from edible wild plants that induces iron-dependent ferroptosis-like cell death in HL-60 cells by decreasing the expression of GPX4 and glutathione. In contrast, sulfasalazine (SSZ), a clinically used anti-inflammatory drug, induces ferroptosis through the system xc-. In this study, we investigated the synergistic effects of these 2 compounds on 3 human breast cancer cell lines (HBC-5, MCF-7, and MDA-MB-231). EDBD-induced cell death was relieved by the lipid peroxidation inhibitor ferrostatin-1 and the iron chelator deferoxamine mesylate (DFOM), indicating that EDBD induced ferroptosis-like cell death. Moreover, cotreatment with EDBD and SSZ synergistically induced cell death in all 3 cell lines. Because the cytotoxicity of the cotreatment was inhibited by DFOM and ferrostatin-1, the combination of EDBD and SSZ synergistically induced ferroptosis. Collectively, EDBD enhanced the effects of SSZ as a clinical anti-inflammatory and anticancer drug candidate.

3,6-Epidioxy-1,10-bisaboladiene induces ferroptosis-like cell death through lipid peroxidation.

3,6-Epidioxy-1,10-bisaboladiene (EDBD) is a bisabolane sesquiterpene endoperoxide that was isolated from an edible wild plant in Japan, Cacalia delphiniifolia. It showed partially apoptotic cell death through caspase activation against HL-60 cells. However, almost all of the cells had necrotic morphology. Thus, we examined the mechanism of action of EDBD on necrotic cell death. EDBD induced ferrous ion-dependent cell death which causes cell membrane damage, and its cell death form was like H2O2-induced necrosis in HL-60 cells. The oxidative stress-induced necrosis inhibitor IM-54 prevented EDBD-induced cell death, but it was not blocked by either caspase inhibitor, z-VAD-fmk, or necroptosis inhibitor, necrostatin-1. Furthermore, EDBD induced lipid peroxidation in a time- and dose-dependent manner and was inhibited with both ferrostatin-1 and α-tocopherol. EDBD also downregulated GPX4, the primary cell defense protein against lipid peroxidation, and decreased GSH levels. Taken together, these results suggest that EDBD induces ferrous ion-dependent ferroptosis-like cell death through lipid peroxidation.

Cytotoxicity and induction of G1 phase cell cycle arrest in human acute promyelocytic leukemia HL60 cells by indole alkaloids isolated from Dialium corbisieri seeds.

The phytochemical investigation of Dialium corbisieri seeds led to the isolation of five monoterpenoid indole alkaloids along with a phytoserotonin, 1-6 and among the known compounds, the spectroscopic data of (5S)-methoxy-akuammiline (1) was reported for the first time. The structures were elucidated based on nuclear magnetic resonance spectroscopic techniques such as ultraviolet, infrared, high-resolution electrospray ionization time-of-flight mass spectrometry, and electron-capture dissociation spectrum calculations. The isolated compounds were evaluated for their cytotoxicity and cell progression in the human acute promyelocytic leukemia HL60 cell line.

Synthesis of polyozellin, a prolyl oligopeptidase inhibitor, and its structural revision.

Polyozellin is a p-terphenyl compound which was isolated from Polyozellus multiplex, and exhibits an inhibitory activity against prolyl oligopeptidase (POP). Its structure was assigned as 1 having a p-terphenyl skeleton including a p-substituted dibenzofuran moiety by spectroscopic analyses and chemical means. This paper describes the total syntheses of the proposed structure 1 for polyozellin and its o-isomer 2, revising the structure of polyozellin to the latter. These syntheses involved a double Suzuki-Miyaura coupling using chlorophenylboronic acid as a common key building block, and Cu mediated Ullmann cyclization as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated.

New triterpene saponins from the roots of Acacia macrostachya (Mimosaceae).

Four new oleanane-type saponins, macrostachyaosides A, B, C, and D (1-4) were isolated from the roots of Acacia macrostachya. Their structures were elucidated on the basis of extensive 1D- and 2D-NMR data and HR-ESI-MS analyses. At concentrations of 100 µM of each compounds, none of the tested compounds caused a significant growth reduction against HL60 cells.

New eremophilane and dichlororesorcinol derivatives produced by endophytes isolated from Ficus ampelas.

The novel compound, 11-O-methylpetasitol (1), was isolated from Penicillium sp. N-175-1, and two new compounds, cosmochlorins D (5) and E (6), were isolated from Phomopsis sp. N-125. In addition, three known eremophilane sesquiterpenes, sporogen-AO1 (2), petasol (3) and 6-dehydropetasol (4), were isolated from Penicillium sp. N-175-1. The structures of 1, 5 and 6 were elucidated by a combination of extensive spectroscopic analyses, including 2D NMR, high-resolution electrospray ionization time-of-flight mass spectrometry (HRESITOFMS) and chemical reactions. Compounds 2, 3, 5 and 6 exhibited cytotoxicity to HL60 and 2 and 3 to HeLa cells. Furthermore, 2 and 3 showed robust growth-restoring activity of a Saccharomyces cerevisiae (cdc2-1 rad9Δ) mutant strain, whereas 5 and 6 exhibited minor growth-restoring activity in this strain. Thus, these compounds may inhibit the growth of HL60 and HeLa cells by blocking the cell cycle, and they may be utilized as new lead compounds that act as inhibitors of survival signal transduction pathways.