Inhibition of aberrant proliferation and induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural phytochemicals

Oncol Rep. Mar-Apr 1998;5(2):311-5. doi: 10.3892/or.5.2.311.

Abstract

Aberrant proliferation and modulated apoptosis leading to impaired cellular homeostasis represent crucial early events in the multi-step carcinogenic process. Regulation of these perturbed biomarkers may predict efficacious prevention of cancer development. Present experiments on non-cancerous human mammary epithelial 184-B5 cells were designed to examine whether i) exposure to suspect environmental human carcinogen Benzo (a) pyrene (BP) alters the status of cell proliferation and apoptosis and ii) BP-induced alterations are modulated in response to select natural phytochemicals that inhibit rodent mammary tumorigenesis. Flow cytometric analysis, cellular immunoreactivity to proliferation specific and apoptosis specific gene products and anchorage-dependent colony formation represented quantitative endpoints. Cruciferous glucosinolate indole-3-carbinol (I3C), tea polyphenol (-) epigallo catechin gallate (EGCC) and soy isoflavone genistein (GEN) represented the chemopreventive test compounds. A single 24 h exposure to 39 lM BP resulted in a 50% decrease (P=0.02) in the ratio of quiescent (Q=G0) to proliferative (P=S + M) population in part due to increase in aberrantly proliferative cells. The BP-initiated cells also exhibited an 87.8% inhibition (P=0. 0001) in confluency-associated apoptosis and a concomitant decrease in cellular immunoreactivity to wild-type p53. Simultaneous treatment of cultures with BP + I3C, BP + EGCG and BP + GEN resulted in a 1.8- to 3.4-fold increase (P<0.01) in Q/P ratio and 1.8- to 6. 9-fold increase (P=0.001) in sub G0 (apoptotic) population. The induction of apoptosis was accompanied by enhanced p53 immunoreactivity (P<0.01). In long-term (21 day) experiments, BP treatment induced a 145.3% increase (P=0.001) in anchorage-dependent colony formation. This aberrant proliferation was inhibited by 44.2% to 65.3% (P=0.01) in the presence of the three phytochemicals. Thus, BP-induced aberrant proliferation is inhibited by the natural phytochemicals in part due to regulation of cell cycle progression and induction of p53 dependent apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Benzo(a)pyrene / toxicity*
  • Breast / cytology
  • Breast / drug effects
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Catechin / analogs & derivatives
  • Catechin / pharmacology
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cell Line
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / drug effects*
  • Environmental Pollutants / toxicity
  • Epithelial Cells / drug effects
  • Female
  • Genistein / pharmacology
  • Humans
  • Indoles / pharmacology
  • Precancerous Conditions / pathology
  • Precancerous Conditions / prevention & control*

Substances

  • Anticarcinogenic Agents
  • Environmental Pollutants
  • Indoles
  • Benzo(a)pyrene
  • Catechin
  • epigallocatechin gallate
  • indole-3-carbinol
  • Genistein