Antisense oligonucleotides (ASOs) are a new generation of drugs that can treat human diseases by blocking the transmission of harmful information from the body's genes. In cancer patients, ASOs have the potential to block messages that drive tumors to grow and spread. However, ASOs have not yet been used to treat human cancer. First, they must be transported into cancer cells, but the cancer cells will not let them in.
Finding efficient ASO transport systems is a major challenge for scientists. Cancer cells possess gatekeeper molecules that block the entry of unwanted substances. Although researchers have currently tried a variety of methods to allow ASO to bypass gatekeepers, the success rate is very limited. Recently, in a research report titled "A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides" published in the international magazine Nucleic Acids Research, scientists from Osaka University and other institutions in Japan have discovered a new method to transport ASOs to targets within cancer cells. In the article, researchers synthesized a new compound called L687, which may be able to open special calcium permeability channels on the surface of cancer cells. When calcium ions flow into the cell through open channels, it tells the cell to let ASOs in too.
Figure 1. A new function for TRPC activators regarding ASO trafficking in target cells. (Kohashi, Hiroto, et al. 2024)
"We found that we can use the activator L687 to selectively activate the TRPC3/C6 calcium ion permeability channel." said researcher Hiroto Kohashi, "We then found that the combination therapy of L687 combined with ASO may promote the effective uptake of ASO by cancer cells and mouse tumor cells in laboratory tests. Therefore, the activity of the targeted gene may be inhibited and the efficacy of ASO enhanced. "
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So far, ASOs are mainly used to treat some incurable human diseases and must enter the liver or spinal cord to work. According to the researchers, L687 is an effective drug delivery system that may extend the benefits of ASO therapy to other parts of the body. The researchers said, "We hope that the results of this study may promote the development and transportation of ASOs, as well as the effective progress in the development of similar targeted gene drugs for the treatment of cancer."
The researchers believe that L687 may be a particularly effective way to deliver ASO therapies to lung or prostate cancer. These cancers possess many TRPC3/C6 calcium ion permeable channels, which may be opened by L687, thus revealing new targets for the development of a new generation of therapies. In summary, this study may provide researchers with an opportunity to help develop innovative drug delivery systems to promote the treatment of ASO.
Reference
Kohashi, Hiroto, et al. "A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides." Nucleic Acids Research (2024): gkae245.