Fight Aging!

The present candidate senolytic drugs that produce selective destruction of senescent cells, done as a means to prevent their contribution to the aging process, all arrive from the cancer research community, where they have been tested for their ability to destroy cancerous cells. Piperlongumine is no exception. Here researchers explore more its likely mechanisms, with a focus on the outcome of increased oxidative stress in the cell due to reduced levels of the antioxidant glutathione, among other possibilities. Recent research suggests, however, that increased oxidative stress isn't the mechanism by which cells are pushed into self-destruction by piperlongumine. While adding new information, the research noted below - there is an open access paper in addition to the publicity materials - doesn't greatly clarify the uncertainty over the way in which piperlongumine works, nor does it clarify whether the method is the same for cancerous and senescent cells. Like many drugs, piperlongumine influences a large number of distinct processes in the cell, and there is no comprehensive map of outcomes. The reason why it is interesting as a potential senolytic therapy, versus other cancer drugs where the mechanisms of action are better mapped, is that it has far fewer side-effects in comparison.

Scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The secret lies in a chemical called piperlongumine (PL), which has shown activity against many cancers. Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets - in this case how PL interacts with a gene called GSTP1. Viewing the structures helps in developing drugs for those targets. PL converts to hPL, an active drug that silences GSTP1. The GSTP1 gene produces a detoxification enzyme that is often overly abundant in tumors. "We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies."

Glutathione S-transferase pi 1 (GSTP1), is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased glutathione (GSH). This data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at PLs C7-C8 olefin, while PLs C2-C3 olefin was postulated to react with GSH. However, direct evidence for this mechanism has been lacking.

To investigate, we solved the x-ray crystal structure of GSTP1 bound to PL and GSH to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; No covalent bond formation between hPL and GSTP1 was observed. Mass spectrometric (MS) analysis of reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting hPL is not membrane permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL:GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2017/jan/anticancer-plant-westover.html