Abstract
For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+ in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+ enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies.
Highlights
Discovery of new pharmaceutical agents targeting NPC has been a high priority for the scientific community and governmental health agencies in South-East Asia for many years
In order to identify the potent anti-proliferative agents against NPC, hundreds of compounds were evaluated against two human NPC cell lines (NPC-TW0135 and HONE-136).The results showed that several ACG compounds could effectively inhibit the growth of NPC cells with an IC50 in the nanomolar range and could effectively overcome methotrexate resistance
Recent studies suggest that solid tumor cells exhibit increased survival due to ER-stress responses (ESR) caused by an unfavorable microenvironment such as hypoxia, free-radical insult, pH change and misfolded mutated proteins
Summary
Discovery of new pharmaceutical agents targeting NPC has been a high priority for the scientific community and governmental health agencies in South-East Asia for many years. Several molecular pathways have been proposed, such as disruption of mitochondrial complex I13, the generation of superoxide anion and hydrogen peroxide[14], decreases in both cAMP and cGMP levels[15], the induction of cell-cycle arrest[16,17] or apoptotic cell death induced by elevated cytosolic Ca2+ 18. None of these mechanisms are able to fully explain the anti-tumor properties observed of ACGs19. Our findings suggest that THF-ACGs act as effective and selective inducers of the ESR, blocking NPC proliferation and illustrating a previously unappreciated antitumor mechanism that is effective against nasopharyngeal malignancies
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