Over the course of 2000 years, milk thistle (Silybum marianum) has earned a beneficial reputation in matters relating to the liver, kidneys and gall bladder. Its most well known compound, the flavonoid silymarin derived from the seed of the plant, has both antioxidant and anti-inflammatory properties and has been the subject of many animal and human studies that have yielded mixed results. The most recent study of note focused on silibinin, another component of milk thistle, and its effect on cancer cells in mice.

In a study published in the journal Molecular Carcinogenesis,researchers at the University of Colorado Cancer Center treated lung cancer cells in mice with silibinin and found the compound inhibited tumorigenesis in part by targeting the tumor’s microenvironment.

An article published by the University of Colorado Denver explained the foundation and scope of the study, noting that cells are governed by a chain of signals that accumulate and lead to an end product. To manipulate a cell’s end product, one must discover how to break a link in the signaling chain that leads to it.

In the case of this study, tissue with wound-like conditions allowed tumors to grow and spread. The end products in the cell signal chain resulted in cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS)enzymes which played a role in the inflammatory response to perceived wounds and, subsequently, in tumor growth. Early in the signaling chain that led to those unwanted enzymes were STAT1 and STAT3—transcription factors that allowed the blueprint of DNA to bind with proteins that continue the signal cascade, eventually leading to the production of harmful COX2 and iNOS. By stopping STAT1 and STAT3, the chains that led to COX2 and iNOS enzymes were broken, halting the growth of lung tumors.

Researchers at the University of Colorado applied the aforementioned theory to mouse lung cancer cells, treating the cells with silibinin, which subsequently removed the “molecular billboards” that signal wound-like conditions, effectively stopping the spread of lung cancers, the researchers reported.

“This relatively nontoxic substance—a derivative of milk thistle, called silibinin—was able to inhibit the upstream signals that lead to the expression of COX2 and iNOS,” commented Alpna Tyagi, PhD, of the University of Colorado Skaggs School of Pharmacy. Dr. Tyagi works in the lab of University of Colorado Cancer Center investigator Rajesh Agarwal, PhD.

In addition, Dr. Tyagi and her colleagues compared the effects of silibinin to drugs currently in clinical trials for lung cancer. Would drugs that target other signaling pathways—other linked chains—similarly cut into the production of COX2 and iNOS?

It turned out that inhibiting the chains of JAK1/2 and MEK in combination, and also inhibiting the signaling pathways of EGFR and NF-kB in combination, blocked the ability of STAT1 and STAT3 to trap the energy they needed to eventually signal COX2 and iNOS production.

Compared to multi-million dollar lung cancer drugs, naturally-occurring silibinin blocked not only the expression of COX2 and iNOS, but also the migration of existing lung cancer cells.

“Together, we showed that STAT3 and STAT1 could be valuable chemopreventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within tumor itself, and that silibinin inhibits their activation as a plausible mechanism of its efficacy against lung cancer,” the researchers concluded.

“What we showed is that STAT1 and STAT3 may be promising therapeutic targets in the treatment of lung cancer, no matter how you target them,” echoed Dr. Tyagi. “And also that naturally-derived products like silibinin may be as effective as today’s best treatments.”

This research endeavor was supported by a grant from the National Cancer Institute.