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We have identified a group of 8 (among 39) human tumour cell strains deficient in the ability to support the growth of adenovirus 5 preparations treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but able to support the growth of non-treated adenovirus normally. This deficient behaviour defines the Mer- phenotype. Strains having the Mer- phenotype were found to arise from tumours originating in four different organs. Relative to Mer+ strains, Mer- tumour strains showed greater sensitivity to MNNG-produced killing, greater MNNG-stimulated "DNA repair synthesis and a more rapid MNNG-produced decrease in semi-conservative DNA synthesis. Here we report that (1) Mer- strains are deficient in removing O6-methylguanine (O6-MeG) from their DNA after [Me-14C]MMNG treatment (Table 1); (2) Mer- tumour strains originate from tumours arising in patients having Mer+ normal fibroblasts (Fig. 1a, b); (3) SV40 transformation of (Mer+) human fibroblasts often converts them to Mer- strains (Fig. 1c, d); (4) MNNG produces more sister chromatid exchanges (SCEs) in Mer- than in Mer+ cell strains (Fig. 2).

Penitrems are indole diterpene alkaloids best known for their BK channel inhibition and tremorgenic effects in mammals. In a previous study, penitrems A–F (1–5), their biosynthetic precursors, paspaline (6) and emindole SB (7), and two brominated penitrem analogs 8 and 9 demonstrated promising in vitro antiproliferative, antimigratory, and anti-invasive effects in the MTT (MCF-7 and MDA-MB-231), wound-healing, and Cultrex® BME cell invasion (MDA-MB-231) assays, respectively. The study herein reports the novel ability of penitrem A to suppress total β-catenin levels in MDA-MB-231 mammary cancer cells. Nine new penitrem analogs (10–18) were semisynthetically prepared, in an attempt to identify pharmacophores correlated with BK channel inhibition and tremorgenicity of penitrems and decrease their toxicity. The degree of BK channel inhibition was assessed using the nematode Caenorhabditis elegans, and in vivo tremorgenic EC50 was calculated using CD-1 male mice following an Up-and-Down-Procedure (UDP). Although new analogs were generally less active than parent compound 1, some showed no BK channel inhibition or tremorgenicity and retained the ability of penitrem A (1) to suppress total β-catenin levels in MDA-MB-231 cells. Paspaline (6) and emindole SB (7), both lacking BK channel inhibition and tremorgenicity, represent the simplest indole diterpene skeleton that retains the antiproliferative, antimigratory and total β-catenin suppressing effects shown by the more complex penitrem A (1).

Breast cancer (BC) recurrence represents a challenge for survivors who have had their primary tumors surgically excised, and/or have completed radiation, neoadjuvant, or adjuvant therapeutic regimens. Current BC treatments mostly lack the ability to reduce the risk of disease recurrence. About 70% of BC patients will subsequently suffer disease relapse, manifesting as local, regional, or distant tumor recurrence, which clearly underscores the urgent need to discover novel recurrence inhibitors. (−)-Oleocanthal (OC) is a natural phenolic, found so far exclusively in extra-virgin olive oil (EVOO). OC exerts documented bioactivities against diverse cancer types, inflammation, and neurodegenerative diseases. Herein we report the novel activity of daily oral treatment with OC (10 mg/kg) in preventing BC locoregional recurrence in a nude mouse xenograft model generated by orthotopic inoculation with BT-474 cells as a luminal type B model. We further report inhibition of tumor recurrence by OC after completion of a lapatinib neoadjuvant regimen. However, in a recurrence model of triple-negative breast cancer (TNBC), OC treatment (10 mg/kg) did not effectively prevent tumor recurrence, but rather, was seen to significantly reduce the growth of recurrent tumors as compared to vehicle control-treated animals. Inhibition of tumor recurrence was associated with significant serum level reductions of the human BC recurrence marker CA 15-3 at the study end in animals treated with OC. OC treatment upregulated the expression of the epithelial marker E-cadherin and downregulated the levels of the mesenchymal marker vimentin in recurrent tumors vs. untreated control animals. OC treatment also reduced the activation of MET and HER2 receptors, as indicated by reduced phosphorylation levels of these proteins in recurrent tumors vs. controls. Collectively, the results of our studies provide the first evidence for suppression of BC tumor recurrence by oral OC treatment in an animal model for such recurrence, and furthermore, highlight favorable prospects for this natural product to emerge as a first-in-class BC recurrence inhibitor.