Dithiolethiones for cancer chemoprevention: where do we stand?

Abstract

Dithiolethiones are a well-known class of cancer chemopreventive agents; the key mechanism of action of dithiolethiones involves activation of Nrf2 signaling and induction of phase II enzymes. In the past, attention has been focused mainly on 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz), which showed ability as a wide-spectrum inhibitor of chemical carcinogenesis in preclinical models. However, clinical trials of oltipraz have shown questionable efficacy, and at the high doses employed in such studies, significant side effects were observed. Dithiolethiones that are markedly more effective and potent than oltipraz in both induction of phase II enzymes and inhibition of chemical carcinogenesis in preclinical studies have been identified, and these compounds have shown pronounced organ specificity in vivo. Further investigation of these compounds may lead to development of effective and safe agents for cancer prevention in humans.

Figure 1

Names and chemical structures of dithiolethiones discussed in this review. Compound 1, 3H-1,2-dithiole-3-thione; Compound 2, 1,3-dithiole-2-thione; Compound 3, 3H-1,2-dithiole-3-one; Compound 4, 5-methyl-3H-1,2-dithiole-3-thione; Compound 5, 4-methyl-3H-1,2-dithiole-3-thione; Compound 6, 4,5-dimethyl-3H-1,2-dithiole-3-thione; Compound 7, 4-chloro-5-methyl-3H-1,2-dithiole-3-thione; Compound 8, 5-ethyl-3H-1,2-dithiole-3-thione; Compound 9, 4-ethyl-3H-1,2-dithiole-3-thione; Compound 10, 5-tert-butyl-3H-1,2-dithiole-3-thione; Compound 11, 5-[2-dimethylamino)vinyl]-4-methyl-3H-1,2-dithiole-3-thione; Compound 12, 4-phenyl-3H-1,2-dithiole-3-thione; Compound 13, 5-phenyl-3H-1,2-dithiole-3-thione; Compound 14, 5-(4-methoxyphenyl)- 3H-1,2-dithiole-3-thione); Compound 15, 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione; Compound 16, 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-one; Compound 17, 5,6-dihydrocyclopenta[c]-1,2-dithiole-3(4H)-thione; Compound 18, 4,5,6,7-tetrahydrobenzo[c]-1,2-dithiole-3-thione.

Figure 2

The key cancer chemopreventive mechanism of dithiolthiones. Binding of Keap1 to Nrf2 targets Nrf2 for proteasomal degradation. Disruption of the association of Keap1 with Nrf2 by dithiolethiones through interaction with critical Keap1 cysteine residues causes increased nuclear accumulation and ARE binding of Nrf2, leading to increased transcription of Phase 2 genes and other genes and increased cellular protection.