A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

Abstract

Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.

Benzophenones from Betula alnoides with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line

“…The IR spectrum of 5 displayed bands for hydroxy and carbonyl functional groups at 3434 and 1655 cm −1 , respectively. The 1 H and 13 C NMR data of 5 (Tables 2 and 3) were closely comparable to those of 2. However, the upfield shifts of the C-2 (δ C 156.7) and C-3 (δ C 99.9) resonances of 5 compared to their counterparts in 2 [δ C 160.9 (C-2) and 106.6 (C-3)], together with the difference in molecular masses between the two compounds, suggested the presence of an additional ring in 5 as a part of a chromane skeleton.…”

“…The IR spectrum exhibited absorption bands for hydroxy and carbonyl groups at 3451 and 1656 cm −1 , respectively. The 1 H and 13 C NMR spectra of 3 and 4 (Tables 1 and 3) displayed a pair of signals in a ratio of 2:1, which were similar to the 1 H and 13 C NMR signals of 2, suggesting that both compounds are oxidation products of 1. For the minor compound 3, the observation of the COSY correlations H-4″/H-5″/H-6″ and H-8″/H-9″/H-10″ and the HMBC correlations from H 3 -14″ to C-6″, C-7″, and C-8″ confirmed the oxidation of Δ 6 ″ ,7 ″ in 1 to give 3.…”

“…Its IR spectrum showed absorption bands for hydroxy (3408 cm −1 ) and carbonyl (1622 cm −1 ) groups. The 1 H NMR spectrum of 1 (Table 1 16 However, this is the first report of 1 as a natural product that provides complete 13 C and 2D NMR data (Table 3 and Figure 1).…”

Blue-Print Autophagy in 2020: A Critical Review

“…Another interesting research by Fuwa and Sato reports an anticancer activity of the synthetic analog of marine macrolide neopeltolide (isolated from a deep-water sponge Neopeltidae sp. [ 50 ])— 8,9-dehydroneopeltolide ( 8,9-DNP )—in human pancreatic cancer PANC-1 cells [ 51 ]. The authors have shown 8,9-DNP to inhibit cytoprotective autophagy by preventing lipidation of LC3B-I to LC3B-II under starvation conditions.…”

“…The authors have shown 8,9-DNP to inhibit cytoprotective autophagy by preventing lipidation of LC3B-I to LC3B-II under starvation conditions. Even though the drug target was not identified, the generated results suggested that autophagy was inhibited at its early stages and that 8,9-DNP does not interfere with cellular energy-sensing signals [ 51 ].…”