Navigation Links
Researchers shed light on mechanism of action used by anti-cancer drug

Virginia Commonwealth University Massey Cancer Center researchers 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 researchers 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.

According to Grant, sorafenib, or Nexavar which is manufactured by Bayer Pharmaceuticals, has recently been approved for the treatment 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.

Previous findings by Grant’s team, reported 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 found 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 found 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 pr otein 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, according to Grant, when ER stress exceeds a certain threshold, the ER stress response is converted from an adaptive to a pro-death response.

The team observed that exposure of cells to sorafenib resulted in the pronounced phosphorylation of a protein known as eIF2á, a process that serves as a critical brake on protein translation in cells subjected to ER stress. Interestingly, they also found 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 associated with 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.


Source:Virginia Commonwealth University

Related biology news :

1. Researchers discover way to make cells in the eye sensitive to light
2. Researchers find how protein allows insects to detect and respond to pheromones
3. Researchers Uncover Key Step In Manufacture of Memory Protein
4. Researchers reveal the infectious impact of salmon farms on wild salmon
5. Researchers identify target for cancer drugs
6. Researchers discover molecule that causes secondary stroke
7. Researchers find missing genes of ancient organism
8. Researchers trace evolution to relatively simple genetic changes
9. Researchers add new tool to tumor-treatment arsenal
10. UF Researchers Map Bacterial Proteins That Cause Tooth Loss
11. VCU Researchers Identify Networks Of Genes Responding To Alcohol In The Brain

Post Your Comments:

(Date:11/9/2015)... Nov. 09, 2015 ... of the "Global Law Enforcement Biometrics ... --> ) has announced ... Enforcement Biometrics Market 2015-2019" report to ... Markets ( ) has announced the ...
(Date:11/2/2015)... PARK, Calif. , Nov. 2, 2015  SRI ... $9 million to provide preclinical development services to the ... the contract, SRI will provide scientific expertise, modern testing ... wide variety of preclinical pharmacology and toxicology studies to ... --> The PREVENT Cancer Drug Development ...
(Date:10/29/2015)... 2015 Daon, a global leader in mobile ... a new version of its IdentityX Platform , ... America have already installed IdentityX v4.0 and ... FIDO UAF certified server component as an ... FIDO features. These customers include some of the largest ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... PA (PRWEB) , ... November 24, 2015 , ... This ... entrepreneurs at competitive events in five states to develop and pitch their BIG ideas ... projects from each state are competing for votes to win the title of SAP's ...
(Date:11/24/2015)... SHPG ) announced today that Jeff Poulton , ... Annual Healthcare Conference in New York City ... (1:30 p.m. GMT). --> SHPG ) announced today that ... Piper Jaffray 27 th Annual Healthcare Conference in ... at 8:30 a.m. EST (1:30 p.m. GMT). --> Shire ...
(Date:11/24/2015)... , Nov. 24, 2015  Tikcro Technologies Ltd. (OTCQB: TIKRF) today announced ... 29, 2015 at 11:00 a.m. Israel time, at ... 98 Yigal Allon Street, 36 th Floor, Tel Aviv, ... Eric Paneth and Izhak Tamir to the Board of ... as external directors; , approval of an amendment to certain terms ...
(Date:11/24/2015)...  Twist Bioscience, a company focused on synthetic ... Bioscience chief executive officer, will present at the ... 2015 at 3:10 p.m. Eastern Time at The Lotte New ... --> --> About Twist ... on Twitter. Sign up to follow our Twitter ...
Breaking Biology Technology: