Tissue with wound-like conditions allows tumors to grow and spread. In mouse lung cancer cells, treatment with silibinin（水飞蓟） , a major component² of milk thistle, removed the molecular³ billboards⁴ that signal these wound-like conditions and so stopped the spread of these lung cancers, according to a recent study published in the journal Molecular Carcinogenesis（致癌作用） . Though the natural extract has been used for more than 2,000 years, mostly to treat disorders⁵ of the liver and gallbladder（胆囊） , this is one of the first carefully controlled and reported studies to find benefit.

How it works

Basically, in a cell there can be a chain of signals, one leading to the next, to the next, and eventually to an end product. And so if you would like to eliminate an end product, you may look to break a link in the signaling chain that leads to it. The end products COX2 and iNOS are enzymes⁶ involved with the inflammatory response to perceived wounds -- both can aid tumor¹ growth. Far upstream in the signaling chain that leads to these unwanted enzymes are STAT1 and STAT3. These transcription factors allow the blueprint⁷ of DNA⁸ to bind⁹ with proteins that continue the signal cascade¹⁰（层叠，小瀑布） , eventually leading to the production of harmful COX2 and iNOS.

Stop STAT1 and STAT3 and you break the chain that leads to COX2 and iNOS -- and the growth of lung tumors along with them.

"This relatively¹¹ nontoxic substance -- a derivative¹²（衍生物） of milk thistle, called silibinin -- was able to inhibit¹³ the upstream signals that lead to the expression of COX2 and iNOS," says Alpna Tyagi, PhD, of the University of Colorado Skaggs School of Pharmacy¹⁴. Tyagi works in the lab of University of Colorado Cancer Center investigator¹⁵ Rajesh Agarwal, PhD.

In addition, Tyagi and collaborators 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 inhibiting¹⁶ 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 these multi-million dollar drugs, naturally-occurring silibinin blocked not only the expression of COX2 and iNOS, but also the migration¹⁷ of existing lung cancer cells.

"What we showed is that STAT1 and STAT3 may be promising¹⁸ therapeutic¹⁹ targets in the treatment of lung cancer, no matter how you target them," Tyagi says. "And also that naturally-derived products like silibinin may be as effective as today's best treatments."

This work was supported by NCI RO1 grant CA113876.