A novel plant toxin, persin, within vivoactivity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells

Abstract

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor -, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland -specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G 2 -M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers. [Mol Cancer Ther 2006;5(9):2300 -9]

Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

“…MCF-7 cells stably overexpressing human BCL-2 have been previously described (Butt et al, 2006). 4-OHT was purchased from Sigma-Aldrich (St Louis, MO, USA).…”

The Cytotoxic Effects of Novel Persin Analogues on a Breast Cancer Cell Line

“…Chemotherapeutic properties of plant chemicals, or phytochemicals, have been studied and some found to have antitumor activity, providing effective therapeutic treatment. According to Butt et al (2006), the most widely used phytochemicals are taxanes, such as paclitaxel and its derivatives, which are effective against some types of breast, ovary, and other cancers.…”

“…Persin is a phytochemical that has been isolated from the avocado plant (Persea americana); persin is synthesized in the plant's idioblast oil cells from long-chain fatty acids, presumably as an insecticide and fungicide (Butt et al, 2006;Rodriguez-Saona and Trumble, 2000). It was previously shown that ingestion of avocado leaves by lactating livestock causes mastitis and decreased milk production, associated with necrosis of the secretory epithelium of mammary glands, as well as interstitial edema, congestion and hemorrhage (Kingsbury, 1964, pp.…”

“…In addition to mammary gland necrosis and reduced milk production, apoptosis has been shown to occur in the mammary glands of persin-treated lactating mice (Butt et al, 2006). In the estrogen receptor positive MCF-7 and T-47D human breast cancer cell lines, persin treatment inhibited cell proliferation, resulted in decreased expression of cyclins A, D1, and B1, and led to cell cycle arrest in G2-M phase (Butt et al, 2006).…”

“…In the estrogen receptor positive MCF-7 and T-47D human breast cancer cell lines, persin treatment inhibited cell proliferation, resulted in decreased expression of cyclins A, D1, and B1, and led to cell cycle arrest in G2-M phase (Butt et al, 2006). Taxane cancer drugs, such as paclitaxel, also induce G2-M phase arrest via microtubule stabilization and bundling, leading to apoptosis (Butt et al, 2006). Like paclitaxel, persin treatment resulted in rearrangement of cytoskeletal microtubules into thick, peripheral bundles instead of radiating from the center, as well as an overall increase in polymerized tubulin.…”