A molecule previously thought to play a purely structural and inert role in cells is actually involved in multidrug resistance in cancer, US scientists reported on Friday.

Using antagonists for this molecule, the researchers were able to sensitize drug resistant breast cancer cells to chemotherapeutic drug treatment, said researchers in a study published in an issue of the Journal of Biological Chemistry.

Multidrug resistance is very common in most types of cancers, making it one of the leading problems in cancer therapy. It is often caused by an increase in the cell's production of proteins that transport drugs out of the cell, preventing the drugs from combating cancer.

In previous studies, the researchers led by Bryan Toole at the Medical University of South Carolina noticed that small pieces of a polysaccharide called hyaluronan were able to sensitize drug-resistant breast cancer cells to several different chemotherapeutic drugs.

They believed that the polysaccharide oligomers were binding toa receptor for hyaluronan (called CD44) and preventing it from initiating a signaling cascade that would result in drug resistance.

In their new paper, the researchers report on further findings which indicate that hyaluronan increases the cellular production of a multidrug transporter protein by binding to CD44.

Using multidrug-resistant human breast carcinoma cells, the researchers demonstrate that hyaluronan acts upstream and downstream of phosphoinositide 3-kinase and that both hyaluronan and phosphoinositide 3-kinase stimulate expression of the multidrug transporter, MDR1, and induce drug resistance.

They discover that antagonist molecules that bind to hyaluronanand prevent it from interacting with CD44 were able to sensitize multidrug resistant breast cancer cells to chemotherapeutic drugs.

They also find that increasing hyaluronan synthesis in cells increased resistance to drug treatment.

"This pathway may also be important in progression of other malignant characteristics. These results illustrate the potential importance of hyaluronan as a therapeutic target in multidrug-resistant carcinomas," the paper said.

Most scientists have thought of hyaluronan as a structural and inert molecule. In adult tissues, it assists in tissue hydration and in biophysical properties such as resilience, and forms a template to which matrix proteins attach and form important extracellular structural complexes.

It is very surprising that hyaluronan is involved in drug resistance, according to Toole.

Hyaluronan also accumulates around the outside of cells during disease processes such as early atherogenesis, persistent inflammation, and cancer. In recent years, however, hyaluronan hasalso been shown to induce signaling pathways in inflammatory, embryonic and cancer cells.

"Our work indicates that hyaluronan antagonists, for example small hyaluronan oligomers, reverse the malignant properties of cancer cells, including proliferation, invasiveness, and drug resistance," Toole said in a statement.

"Hyaluronan oligomers are non-toxic, non-immunogenic, and readily applicable to several proliferative disease processes, especially cancer. We are hoping that hyaluronan antagonists can be used in conjunction with chemotherapy such that much lower and less toxic doses of chemotherapeutic agents can be used."

Source: Xinhua