Necrosis used to kill cancer

A University of Pennsylvania research team has shown that it can kill tumor cells in mice by necrosis, rather than by inducing apoptosis, by giving them alkylating agents that block their energy supply. The authors of the study, which appears in the advanced online edition of Genes and Development, say the finding may give researchers another important mechanism with which to destroy cancer cells.Craig Thompson and colleagues at the university's Abramson Family Cancer Research Institute bred mice to be deficient in two genes that help regulate death by apoptosis, p53, and BCL-2. In a series of experiments, the team proved that alkylating agents caused necrotic death in the tumor cells, according to the report.The group also showed that providing another source of energy to both apoptotic-deficient tumor cells and tumors from wildtype apoptotic-competent mice prevented both groups of cells from dying, according to the article.Although other researchers had already discovered some parts of the chain events demonstrated by Thompson's group, theirs is the first to put together the complete mechanism, according to Jean Wang, an apoptosis researcher and biology professor at the University of California at San Diego.Wang said that previous work has shown that the alkylating agents in chemotherapy drugs not only induce apoptosis, but also damage tumor cells' DNA. Thompson's group showed that in its specially bred mice, this injury activated the DNA repair protein poly(ADP-ribose) polymerase (PARP).Other investigators had shown that PARP depletes nicotinamide adenine dinucleotide (NAD), a coenzyme necessary for the metabolism of ATP. When Thompson's lab removed tumor cells from the mice and treated them with alkylating agents, the cells died as soon as all the NAD was consumed.This new technique worked, Thompson said, only because a mature tumor cell gets all of its energy from the metabolism of glucose by oxygen. “Most normal cells can live on the catabolism and the production of [ATP precursor] ADP from multiple substrates,” he told The Scientist.Andrei Gudkov, professor of molecular biology at Case Western Reserve University, said that Thompson's results are the latest evidence supporting an ongoing paradigm shift in cancer biology. Apoptosis now seems less important than previously believed, he said, while necrosis is far from the unimportant and irrelevant mechanism it had been presumed to be.Thompson and Wang said the results show that if scientists could find new ways to activate PARP or deplete NAD, they could kill tumor cells without damaging the cells' DNA. That would eliminate several bad side effects, including creating further mutations that sometimes lead to additional cancers. “Craig essentially tells all of us that if we have a way to deplete NAD, the essential metabolite, specifically in cancer cells, they should just all drop dead,” Wang told The Scientist, “whereas normal cells may not, because they have their own pool of NAD in the mitochondria, which is in the form of NADH. So I think that's a totally valid point.”Gerard Evan, a professor of at the University of California at San Francisco, said he is not so sure that the study shows that the tumor cells are dying purely of necrosis. He told The Scientist that some apoptosis might still be going on alongside the necrosis, using apoptotic regulators Thompson did not knock out, particularly ones not yet discovered. Thompson acknowledged that possibility. Evan also questioned the practical importance of Thompson's necrosis demonstration. For one thing, the mice he used may not occur naturally in nature, in part because he has never seen a tumor cell deficient in both of BCL-2's proteins, bax and bak. “When and where might this actually happen?” Evan asked. Moreover, if apoptosis normally kills tumor cells before necrosis ever gets a chance to, necrosis may be largely irrelevant, he said.Thompson said that necrosis is the more promising mechanism than apoptosis because death by apoptosis suppresses the immune system, while death by necrosis activates it, providing an additional way to kill tumor cells. While that is probably true of sporadically occurring apoptosis, Evan said, it is not true of the massive apoptotic death normally caused by chemotherapy and radiotherapy, in which so much cellular debris piles up that the immune system sends in phagocytic white cells to digest and remove it.Correction (posted May 18): When originally posted, this story incorrectly named Jean Wang. The Scientist regrets the error.Editor's note: See a letter on this story.

Necrosis used to kill cancer

DNA alkylation destroys tumor cells in mice deficient in p53 and BCL-2

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