The cytotoxic macrolide FD-891 induces caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in human leukemia Jurkat cells

Abstract

The 16-membered macrolide FD-891 exerts cytotoxicity toward several cancer cell lines. In this study, we showed that FD-891 induces apoptosis in various human cancer cell lines. Human leukemia Jurkat cells were highly sensitive to FD-891, exhibiting caspase activation and mitochondrial release of cytochrome c into the cytosol at early time points after exposure to FD-891. By contrast, Jurkat cells deficient in caspase-8 were resistant to FD-891-induced apoptosis and manifested little induction of cytochrome c release as well as caspase-9 processing. Consistent with these results, the overexpression of the Bcl-2 family member Bcl-x L or the caspase-8 modulator c-FLIP L markedly prevented FD-891-induced apoptosis. These results clearly demonstrate that FD-891 triggers caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in Jurkat cells.

Cloning and Characterization of the Biosynthetic Gene Cluster of 16‐Membered Macrolide Antibiotic FD‐891: Involvement of a Dual Functional Cytochrome P450 Monooxygenase Catalyzing Epoxidation and Hydroxylation

“…Among various human cancer cell lines, four leukemia cell lines, HL-60, Jurkat, THP-1, and U-937 were highly sensitive to FD-891. [2] Further biochemical studies of FD-891 in Jurkat cells suggested that FD-891 strongly induces apoptosis of Jurkat cells through mitochondrial release of cytochrome c as well as caspase-9 processing triggered by caspase-8 activation. This apoptosis-signaling pathway caused by FD-891 was thus distinct from the other caspase-dependent apoptosis by chemotherapic drugs such as doxorubicin, etoposide, and vincristine.…”

Acyltransferase Domain Exchange between Two Independent Type I Polyketide Synthases in the Same Producer Strain of Macrolide Antibiotics

“…[1] FD‐891 ( 1 ) shows potent cytotoxicity against leukemia cells, including HL‐60, Jurkat, THP‐1, and U‐937 cell lines [2] . The compound induces apoptosis of Jurkat cells by inducing mitochondrial release of cytochrome c and triggering caspase‐9 processing by activating caspase‐8 [2b] . It has also been proposed to induce apoptosis by the cell‐cycle arrest at the G 2 /M phase [3] .…”

A Concise and Unified Strategy for Synthesis of the C1–C18 Macrolactone Fragments of FD-891, FD-892 and Their Analogues: Formal Total Synthesis of FD-891

“…Their structures were first proposed to be 18-membered macrolides , but were later reassigned as 16-membered macrolides by Eguchi et al., as shown in Figure A . These macrolides have been reported to show several biological activities, , including cytotoxic activity against several tumor cell lines, when used at ten nanomolar for FD-891, 1 , and micromolar for FD-892, 2 , concentration ranges. Thus, FD-891, 1 , shows more than 100 times the potency of FD-892, 2 .…”