| | Category | ME | L18 | Proteasome Inhibition and Apoptosis by DSF-analogue #39 in MDA- |
| | MB-231 cells |
| | Abstract | Copper is one of the most crucial elements in tumor cell growth because it |
| | is required for several molecular processes in angiogenesis, which is |
| | essential for tumors to spread and metastasize. It is known that there are |
| | higher concentrations of copper in cancer cells than normal cells creating |
| | a differentiation between these cells, which provides a mechanism of |
| | using copper to target only cancer cells as an anticancer strategy. In |
| | recent studies, it has been found that Disulfiram (DSF), a clinically used |
| | medicine for the treatment of alcoholism, is able to bind to copper forming a |
| | potent DSF- Cu conjugate that inhibits proteasome activity and induces |
| | apoptosis in human breast cancer cells. However, clinical use of DSF for |
| | the treatment of cancer is limited because of its toxicity to normal cells. As |
| | well, DSF irreversibly inhibits aldehyde dehydrogenase and other |
| | enzymes, causing toxicities, which makes it a disadvantage considering its |
| | anticancer effects. In this study, I am trying to investigate whether a |
| | variety of DSF analogues are able to bind to copper and form a complex |
| | that produces apoptotic cancer cell death through the inhibition of the |
| | proteasome, as well as have less toxicity to normal cells. |
| | |
| | MDA-MB-231 breast cancer cells were cultured, and incubated with |
| | different concentrations of the DSF analogues coupled with copper. MTT |
| | assays were taken to determine the effects of the compounds and copper |
| | to the proliferation of the breast cancer cells. A Western Blot Analysis |
| | was conducted to determine proteasome inhibition, followed by a |
| | Proteasomal Chymotrypsin- like activity assay demonstrating the effects of |
| | the DSF analogues-copper mixtures on the proteasome. A cellular |
| | morphology analysis was performed as well. |
| | |
| | It has been demonstrated that designated DSF analogue #39 with copper |
| | was the most potent compound-copper conjugate with ~100% inhibition of |
| | MDA-MB-231 cells at concentrations of 1 um – 10 um, even stronger than |
| | DSF-Cu, which was used as a positive control. For breast cancer cells |
| | treated with #39-Cu, there was inhibition of the proteasomal CT-like |
| | activity, and through Western blot an accumulation of ubiquitinated proteins |
| | and PARP cleavage was seen. Preliminary tests also showed that the |
| | DSF analogue #39 has similar toxicity to the MCF-10A normal breast cell |
| | line as the DSF-Cu complex. |
| | |
| | In Conclusion, the designated DSF analogue #39 with copper had potent |
| | anti-proliferation effects through the inhibition of proteasome activity in |
| | cultured breast cancer cells even greater than the DSF-Cu complex, while |
| | it had similar toxicity to normal cells. However, since DSF has multiple |
| | toxicities, further toxicity studies of #39-Cu should be conducted using a |
| | different model. Overall, the data presented here suggests that the DSF- |
| | analogue #39 after coupled with Cu, is a promising complex for further |
| | tests to be a useful anti-tumor drug. |
| | |
| | |