Cancer drugs induce premature aging in tumor cells

December 17, 2001

UIC researchers have found that chemotherapy can permanently arrest the growth of tumor cells, countering a long-held view that the only way to stop cancer is to kill the proliferating cells. The tumor cells that stop dividing bear all the characteristics of senescent, or aged, cells - but that has both advantages and disadvantages.

The findings appear online in the early edition of the Proceedings of the National Academy of Sciences and will be published in the Jan. 8 issue of the journal.

"Drug-induced arrest of cell division has long been considered only a stop-gap measure, because it was presumed the cells would eventually repair their damage and go on to divide again after treatment," said Igor Roninson, lead author of the study and professor of molecular genetics in the UIC College of Medicine. "But we've found that many treated tumor cells that stop dividing don't start multiplying again later."

In the study, the key part of which was carried out by Bey-Dih Chang, research assistant professor, the investigators treated colon cancer cells with the commonly used anticancer drug doxorubicin. As happens with chemotherapy in cancer patients, some of the cells died, but others either survived and continued to grow or survived but ceased dividing altogether.

The researchers found that the cells that stopped dividing closely resembled normal cells that have lost their ability to grow because of senescence, the process of cellular aging. As Roninson's group earlier reported, many other cancer drugs besides doxorubicin also induce features of senescence in cancer cells, as does radiation therapy.

Using powerful genetic technology called cDNA microarrays, Roninson's team was able to identify molecular changes in the senescent colon cancer cells.

Specifically, they found that the cells turned on multiple genes, of which about 10 were capable of halting cell growth.

Some of these genes, known as tumor suppressors, function in normal cells but are shut off when cancer develops. The onset of senescence reactivates these genes, shutting down cell division. Proteins encoded by some of the growth-inhibitory genes are known to act at a distance, stopping the growth of other tumor cells in the vicinity.

"But drug-induced senescence of tumor cells is a mixed blessing," Roninson said.

According to Roninson, the senescent cells not only activated genes that inhibit cell division, they also turned on genes that stimulate, rather than prevent, the growth of neighboring cells, as well as the p21 gene. In previous work, Roninson's laboratory had shown that p21 turns on a host of genes linked to numerous diseases associated with old age, including Alzheimer's. Such genes were activated in the senescent colon cancer cells as well.

Not all chemotherapeutic drugs activate these harmful genes, said Roninson. In a separate study, recently published in the inaugural issue of a new journal, Cancer Biology and Therapy, Roninson and colleagues found that retinoids, derivatives of vitamin A, induce senescence and activate tumor- suppressing genes in breast tumor cells but do not turn on either p21 or any of the genes that contribute to cancer or diseases of old age.

Based on those findings, Roninson said it should be possible to design novel drugs that induce tumor cell senescence but not its undesirable side effects.

Other authors of the Proceedings of the National Academy of Sciences study were UIC researchers Mari Swift, Mei Shen, Jing Fang and Eugenia Broude. UIC researchers Milos Dokmanovic, Jing Fang, Chang and Roninson authored the Cancer Biology and Therapy article.

This research was funded by the National Institutes of Health and the Illinois Division of the American Cancer Society. The Mary Kay Ash Charitable Foundation also supported the study reported in Cancer Biology and Therapy.

University of Illinois at Chicago

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