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:
*Name:
*Comment:
*Email:


(Date:3/23/2017)... Research and Markets has announced the addition of the ... to 2025" report to their offering. ... The Global Vehicle Anti-Theft System Market ... the next decade to reach approximately $14.21 billion by 2025. ... for all the given segments on global as well as regional ...
(Date:3/20/2017)... , March 20, 2017 PMD Healthcare announces ... spirometer and Wellness Management System (WMS), a remote, real-time ... in 2010, PMD Healthcare is a Medical Device, Digital ... mission dedicated to creating innovative solutions that empower people ... that intent focus, PMD developed the first ever personal ...
(Date:3/7/2017)... 7, 2017 Brandwatch , the leading social intelligence ... Prince,s Trust to uncover insights to support its reporting, help ... The UK,s leading youth charity will be using Brandwatch Analytics ... get a better understanding of the topics and issues that are ... ...
Breaking Biology News(10 mins):
(Date:3/27/2017)... , March 27, 2017 The new ... a comprehensive library of reports on Valero Energy , ... fuels and petrochemical industries. ...      (Logo: http://photos.prnewswire.com/prnh/20160330/349511LOGO) ... production to go green. Ethanol today, even though touted as ...
(Date:3/27/2017)... March 27, 2017 DarioHealth Corp. (NASDAQ: DRIO), ... and big data solutions, today announced that it is ... option for U.S. consumers who want to have their ... has signed strategic alliance agreements with partners across the ... benefits, and if approved, will supply and bill the ...
(Date:3/24/2017)... , Mar. 24, 2017 Research and ... Cell (hESC) Research - Global Strategic Business Report" report to ... ... (hESC) Research in US$ Million. Annual estimates and forecasts are provided ... derived from primary and secondary research. The report ...
(Date:3/24/2017)... LEXINGTON, Mass. , March 24, 2017 ... pipeline of immune checkpoint antibodies and cancer vaccines, today ... The 7 th  Annual William Blair and Maidstone ... Event Space Alexandria Center in New York, ... March 29 at 9:40 am: ...
Breaking Biology Technology: