Cancer cells don’t differ too much from normal cells, so it is an ongoing challenge to develop methods of killing of carcinoma cells and not host cells. However, researchers of 熊本大学 (Kumamoto University) of Japan recently attached a powerful cell disrupter (killer), methyl-ß-cyclodextrin (M-ß-CyD), to a molecule that interacts heavily with tumor cells, folic acid, to seek out and destroy cancer without harming the host.
M-ß-CyD disrupts the cell membrane by removing cholesterol from the lipid rafts killing the cell in the process. Many tumor cells were found to overexpress folate (folic acid) receptors (FR); therefore, folate was attached to M-ß-CyD (making FA-M-ß-CyD) for tumor selectivity. To test this new compound’s anti-tumor activity, KB and A549 cells were targeted. KB cells are tumor cells that form keratin (main part of human hair and nails) and express FR. A549 cells are tumor cells that are associated with lung alveoli and do not express FR.
The anti-tumor effect and selectivity of FA-M-ß-CyD was significant as it reduced cell viability by up to 80% in KB cells and fractionally affected cell viability in A549 cells (viability reduced 15% at the highest concentration). This showed that cells were only killed if they expressed the folate receptor, and those that were killed were hit hard. Similar results were seen when tested in vivo using mice. Mice injected with FA-M-ß-CyD survived at least 140 days without cancer relapse, which is much greater than the results seen with doxorubicin (most died within 70 days), a popular chemotheraputic drug.
To test if the FA-M-ß-CyD was inducing apoptosis in the affected cells, caspase 3/7 (important up-regulators of cell suicide) activity was monitored using a fluorescence assay. The addition of FA-M-ß-CyD showed no activation of caspase 3 or 7 indicating the mechanism of cancer cell slaughter was independent of the apoptosis pathway. This was a good sign as it meant the effects of FA-M-ß-CyD could not be mitigated by an anti-apoptotic response of the tumor cell.
Finally, FA-M-ß-CyD was tested for safety against red blood cells. Up until the highest concentrations (>8 mM), less than 5% of red blood cells hit with FA-M-ß-CyD were affected. It was only at 10.9 mM was 50% hemolysis seen. This meant FA-M-ß-CyD had very low irritancy to red blood cells.
This study presents FA-M-ß-CyD as a novel, selective, and powerful anti-cancer drug with effects rivaling chemotherapy treatments used today. If this antitumor agent shows promise in humans, it may well replace doxorubicin.
Risako Onodera, Keiichi Motoyama, Ayaka Okamatsu, Taishi Higashi, Hidetoshi Arima. Potential use of Folate-appended Methyl-β-Cyclodextrin as an Anticancer Agent. Scientific Reports, 2013.
From me to you: Sorry about the lateness of the last few articles everyone. Heavy maintenance has been going on this week in my house making it hard to focus. However, I think they’re done tonight!