Abstract
The core of solid tumors is characterized by hypoxia and a nutrient-starved microenvironment and has gained much attention as targets of anti-cancer drugs. In the course of search for selective growth inhibitors against the cancer cells adapted to nutrient starvation, epidithiodiketopiperazine DC1149B (1) together with structurally related compounds, trichodermamide A (2) and aspergillazine A (3), were isolated from culture extract of marine-derived Trichoderma lixii. Compounds 1 exhibited potent selective cytotoxic activity against human pancreatic carcinoma PANC-1 cells cultured under glucose-starved conditions with IC50 values of 0.02 µM. The selective index of the compound 1 was found to be 35,500-fold higher for cells cultured under glucose-starved conditions than those under the general culture conditions. The mechanistic analysis indicated that compound 1 inhibited the response of the ER stress signaling. In addition, these effects of compound 1 could be mediated by inhibiting complex II in the mitochondrial electron transport chain.
Highlights
Solid tumors contain hypoxic and nutrient-starved regions due to the abnormal cell proliferation coupled with the defective and disorganized vascular supply [1]
We present the isolation of epidithiodiketopiperazine DC1149B (1), and structurally related but inactive compounds, trichodermamide A (2) and aspergillazine A (3) isolated from the culture extract of marine-derived Trichoderma lixii., and the cytotoxic activity of compound 1 on nutrient-starved cancer cells, and propose the plausible mechanism of its action
The bioassay-guided separation of the active 90% MeOHsoluble portion from culture extract of marine-derived Trichoderma lixii 15G49-1 led to the isolation of DC1149B (1), trichodermamide A (2), and aspergillazine A (3) (Fig. 1)
Summary
Solid tumors contain hypoxic and nutrient-starved regions due to the abnormal cell proliferation coupled with the defective and disorganized vascular supply [1]. The cancer cells that have adapted to this tumor microenvironment are assumed to develop aggressive phenotype, impaired angiogenesis, and drug resistance [2, 3]. Since the hypoxic and nutrient-starved tumor microenvironment differs significantly from the normal tissues, the compounds with selective cytotoxicity against the cancer cells in tumor microenvironment would have great therapeutic potential. The marine flora and fauna are a rich source of therapeutic drugs because of their chemical and biological diversity. Some of the marine-derived compounds have been reported
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