Selective Depletion of Mutant p53 by Cancer Chemopreventive Isothiocyanates and Their Structure−Activity Relationships

Abstract

Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally-occurring ITCs selectively deplete mutant p53, but not the wild type, and do so via a transcription-independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally-occurring and synthetic ITCs show that depletion is influenced by the ITC side chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild type. 2,2-diphenylethyl ITC, a synthetic ITC and one of the most potent depletors of mutant p53 studied, induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.

Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity

“…Further, PEITC has been shown to have a significant hormetic protective effect due to its ability to induce the expression of various detoxification enzymes and antioxidant molecules, which may contribute to its chemopreventive activity (6). The potent anticancer activity of PEITC is likely attributed to its multiple mechanisms of action, including abrogation of the GSH system, direct binding to certain proteins that are important for cell survival, inducing phosphorylation of p66(Shc), and inhibition of enzymes such as GPX and proteasomes (30,36,41,45). In our study, we found that 10 lM PEITC dramatically inhibited respiration by > 80% in HL-60 and Raji cells with only a 3-h treatment.…”

“…PEITC may also interact with 26S and 20S proteasomes and inhibits the enzyme activity (30). A recent study suggests that this compound seems to bind to mutant p53 and cause its conformational change, thus leading to its depletion (41). Interestingly, PEITC induces phosphorylation of p66Shc, which may translocate to mitochondria and enhance reactive oxygen species (ROS) production and DNA fragmentation (45).…”

PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth

“…A plethora of pre-clinical studies suggest a strong anticancer activity of PEITC. [15][16][17][18][19][20][21][22][23][24] Phase I and II clinical trials are also in progress to test PEITC against lung cancer and leukemia. 25 Hence we evaluated the effects of PEITC on tumor-modulatory immune cells circulating in the blood.…”

Global profiling of lysine reactivity and ligandability in the human proteome

“…Individual lysine residues within functional protein pockets are also susceptible to modification by electrophilic small molecules, including natural products, such as Wortmannin 18 , which targets a lysine in the active sites of PI3K kinases, activated esters that react with a lysine in transthyretin (TTR) 19 , and boronic acid carbonyl antagonists of the apoptosis regulatory protein MCL-1 13 . Additional electrophiles that have been shown to react with proteinaceous lysine residues include dichlorotriazines 20,21 , imidoesters 22 , 2-acetyl- or 2-formyl-benzeneboronic acids 13,23 , isothiocyanates 24,25 , pyrazolecarboxamidines 26,27 , sulfonyl fluorides 28,29 , and vinyl sulfonamides 30 .…”