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Medicineworld.org: Mechanism Of Action Used By Sorafenib

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Mechanism Of Action Used By Sorafenib




Virginia Commonwealth University Massey Cancer Center scientists have uncovered a new mechanism of action of the anti-cancer drug sorafenib, which could stimulate the development of novel regimens in which it is combined with other molecularly targeted agents for patients with blood cancers and solid tumors.

In the new study, led by Steven Grant, M.D., Massey's associate director for translational research and co-leader of the cancer center's cancer cell biology program, VCU scientists identified a mechanism by which sorafenib inhibits protein translation, and which may be involved in reducing expression of pro-survival factors, such as Mcl-1, and other proteins. The findings were published online in the journal Molecular and Cellular Biology on June 4.



Mechanism Of Action Used By Sorafenib

As per Grant, sorafenib, or Nexavar which is manufactured by Bayer Pharmaceuticals, has recently been approved for the therapy of patients with renal cell cancer, the most common form of kidney cancer in adults. It was originally developed as an inhibitor of the oncogene, Raf, which is frequently mutated in numerous cancers, including leukemia. Oncogenes are typically responsible for promoting tumor growth.

Prior findings by Grant's team, published in the Journal of Biologic Chemistry, showed that in human leukemia cells, sorafenib lethality was less a consequence of Raf inhibition, but rather reflected interference with the synthesis of Mcl-1. They observed that sorafenib interfered with Mcl-1 translation, a process in which proteins are synthesized from their constituent amino acids. However, the mechanism by which protein translation was inhibited by sorafenib remained largely unknown.

In the present work, Grant and his team observed that in human leukemia cells, sorafenib induces a process known as endoplasmic reticulum (ER) stress, which results from accumulation of misfolded proteins in the ER. The ER is a subcellular structure which plays a key role in cellular protein disposition. When stressed in this way, the cell responds to the protein load by reducing protein synthesis, increasing levels of protein chaperones, and by accelerating protein degradation. However, as per Grant, when ER stress exceeds a certain threshold, the ER stress response is converted from an adaptive to a pro-death response.

The team found that exposure of cells to sorafenib resulted in the pronounced phosphorylation of a protein known as eIF2a, a process that serves as a critical brake on protein translation in cells subjected to ER stress. Interestingly, they also observed that sorafenib, by virtue of its ability to inhibit Raf, also prevented an increase in expression of a chaperone protein known as Grp78, which is classically induced in the ER stress response, and which helps to resolve stresses linked to increased protein loads. The net effect of these actions was to induce a shutdown of protein synthesis accompanied by a dramatic increase in cell death.

"The notion that sorafenib acts by inhibiting protein synthesis and reducing expression of Mcl-1 suggests that this agent might be logically combined with other targeted agents whose antitumor activity is limited by Mcl-1 expression," Grant said. Several such targeted agents are currently undergoing clinical evaluation in patients with various malignancies.

This work was supported by awards from the National Cancer Institute, the Leukemia and Lymphoma Society of America, the Department of Defense and the V Foundation.


Posted by: Janet    Source




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Virginia Commonwealth University Massey Cancer Center scientists have uncovered a new mechanism of action of the anti-cancer drug sorafenib, which could stimulate the development of novel regimens in which it is combined with other molecularly targeted agents for patients with blood cancers and solid tumors.

Medicineworld.org: Mechanism Of Action Used By Sorafenib

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