The 3,4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers

Abstract

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.

Keywords: N-acetylcysteine; cancer initiation; cancer prevention; estrogen-DNA adducts; estrogens; resveratrol.

Figure 1

Pathway of cancer initiation by estrogens.

Figure 2

Depurinating adducts formed after 10 h (to allow complete depurination of 4-OHE₂-1-N7Gua) by mixtures of lactoperoxidase-activated 4-OHE₂ and 2-OHE₂ reacted with DNA at different ratios. The level of stable adducts formed in the mixtures was less than 1% of the total adducts [37].

Figure 3

Ratios of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates in serum of women at low risk, women at high risk and women diagnosed with breast cancer (p < 0.0001) [46].

Figure 4

Inhibition of estrogen-DNA adduct formation by N-acetylcysteine and resveratrol in (A) MCF-10F cells treated with 4-OHE₂ [30]; and (B) urine from healthy women before and after 3 months of daily ingestion of the two compounds [56].