Annonaceous acetogenin mimic AA005 suppresses human colon cancer cell growth in vivo through downregulation of Mcl-1

Abstract

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.

A Review on Annona muricata and Its Anticancer Activity

“…AA005 is an Annonaceous acetogenin mimic that inhibited tumor growth by promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death in vivo human colon cancer cell lines. In vivo SW620 (human colorectal cancer) and in vitro RKO (poorly differentiated colon carcinoma) cell lines revealed that treatment with AA005 showed down-regulation in Bcl 2 and Mcl-1 [ 55 ]. In silico research on acetogenins reverse ABCB1-mediated multidrug resistance in colon cancer: Annohexocin, Annomuricin, Annomuricin B, Annomuricin E, Annonacin A, Annonacin, Annonacin-10-one, Annonacinone, Annopentocin, Annopentocin B, Annopentocin C, Cis-corossolone, Corossolone SL, Epomuricenin A, Epomuricenin B, Gigantetrocin A, Gigantetronenin, Goniothalamicin, Muricapentocin, Muricatocin A, Muricatocin B, Muricoreacin, Solamin revealed that Annonacin, Annohexocin and Annomuricin showed the highest docking scores [ 56 ].…”

Annonaceous Acetogenin Mimic AA005 Inhibits the Growth of TNBC MDA‐MB‐468 Cells by Altering Cell Energy Metabolism

“…We then investigated the in vivo antitumor efficacy of AA005 in xenograft mice model. Based on the effective therapeutic dose of AA005 in SW620 tumor-bearing nude mice, [22] BALB/c mice bearing the commonly used mouse derived 4T1 xenografts were administered AA005 (0, 1 and 5 mg/kg/day, respectively) for 13 days via intraperitoneal injection. As shown in Figure 5A, administration of AA005 didn't influence the body weight of the mice compared to DMSO (control) treatment, indicating no obviously harmful side effect was caused by AA005.…”

Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme a subunit to treat obesity

“…Consequently, there is an urgent need to explore more safe and effective new compounds for the treatment of obesity, especially those compounds derived from or originating in nature plants. AA005, a recently-identified new annonaceous acetogenin mimic who demonstreated selective antitumor activity in vivo in our previous work [14][15][16][17][18][19] . Interestingly, recent studies have shown that crude leaf extracts from Annonaceae plants have potential anti-diabetes and antioxidant effects, which strongly prompted us to investigate other pharmacological activities of AA005 20 .…”

“…Our previous ndings suggested that high dose of AA005 suppressed human colon cancer cell growth in vivo mediated by apoptosis-inducing factor (AIF) and mitochondrial Complex I components 15,16 . Evidence from other studies showed that muscle-and liver-speci c AIF ablation in mice could counteract the development of insulin resistance, diabetes, and obesity 24 .…”