In Vitro Antitumor Structure–Activity Relationships of threo/trans/threo mono-Tetrahydrofuranic Acetogenins: Correlations With Their Inhibition of Mitochondrial Complex I

Abstract

In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.

Chemopreventive Potential of Annona Muricata L Leaves on Chemically-Induced Skin Papillomagenesis in Mice

“…Previous studies revealed the effect of several acetogenins act as a DNA topoisomerase I poison, arrested cancer cells at the G1 phase and induced apoptotic cell death in a Baxand caspase-3-related pathway, and inhibited NADHubiquinone oxidoreductase (complex I) in mitochondria (Lopez et al, 2001;Yuan et al, 2003;Kojima et al, 2010). It has been reported that the main antitumorous compound, annonacin was effective against various in vitro cancer cell lines as well as in vivo lung-induced cancer (Oberlies et al, 1995;Wang et al, 2002;Tormo et al, 2003). Nowadays, even without any scientific validation, many cancer patients and health practitioners are adding the natural leaf and stem of A. muricata (with over 40 documented naturally-occurring acetogenins including annonacin) as a complementary therapy to their cancer protocols.…”

Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action

“…Oxidative phosphorylation is one of the most cohesive KEGG pathways and it shows strong significant correlations with the agents in a few clades in the R-region (R 5 , P ¼ 1.01 Â 10 À4 and R 4 , P ¼ 1.12 Â 10 À3 ), V-region (V 6, P ¼ 1.33 Â 10 À6 and V 3 , P ¼ 1.72 Â 10 À3 ), and N-region (N 6, P ¼ 4.26 Â 10 À3 and N 13 , P ¼ 0.012). Noteworthy is that many known inhibitors, including the acetogenins, [25][26][27] of mitochondrial complex I, which plays a critical role in the oxidative phosphorylation pathway, are mostly clustered in R 5 and R 4 . The MAPK signaling pathway, on the other hand, is one of the least cohesive KEGG pathways.…”

Evaluation of anti-inflammatory activities of ethanolic extract of Annona muricata leaves

“…Furthermore, AML administered topically has also been observed to show similar activity when compared with the previous studies which were administered orally (Roslida et al, 2010) Basically, there are many reports on studies of Annona muricata L., Annonaceae, in general but only a few on its isolated acetogenins especially acetogenins in the leaves of the plant. A screening program by NCI reported that A. muricata leaves extract showed active toxicity against cancer cells and researchers have been following up on these findings ever since (Tormo et al, 2003). Priorly, acetogenins isolated from A. muricata leaves such as annonacin has been reported to cause significant cell death in various cancer cell lines including skin cancer cell lines (Yuan et al, 2003), whilst muricatocin A and annomuricin A has significantly enhanced cytotoxicity against the A-549 human lung tumor cell line (Wu et al, 1995a;1995b;1995c).…”