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Annonaceous acetogenins are a well-established family of natural products with significant bioactivities,especially high cytotoxic and antitumor activities.AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines,but its in vivo antitumor effects have not been demonstrated so far,and its anticancer mechanisms remain ambiguous.In this study,we investigated the effects of AA005 on human colon cancer cell lines in vivo.Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day,i.p.) for 21 days.AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death.Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005,downregulation of a B-cell lymphoma 2 family protein,myeloid cell leukemia-1 (Mcl-1),was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner.Intriguingly,knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1,and enhanced AA005-mediated lethality,whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells.Finally,silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice,demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005.Taken together,this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo,which is mediated through the downregulation of Mcl-1.