THERAPEUTIC ACTIVITY OF MYCOBACTERIAL CELL WALL-DNA COMPLEX IS DUE TO THE PRESENCE OF MYCOBACTERIAL DNA
Abstract Text
Cell wall skeletons isolated from many bacteria have been shown to possess therapeutic activity. The therapeutic activity of such cell wall skeleton has been attributed to their ability to stimulate the immune system. A number of chemical entities isolated from these cell walls have been shown to be responsible for the reported immunomodulatory activity. These include mumaryl dipeptide, trehalose dimycolate, lipoarabinomannan, lipoteichoic acid, peptidoglycan and glycan. We have recently isolated a cell wall complex from Mycobacterium phlei where mycobacterial DNA in the form of short oligonucleotides is preserved and complexed to the cell wall (MCC). MCC has been shown to be effective in humans for the treatment of cancer. We have therefore characterized the mechanism of action of this cell wall-DNA composition. We have found that MCC appears to exert its anticancer activity by two principal mechanism of action: an indirect effect via the induction of anticancer cytokine synthesis by immune cells (as reported for many cell wall skeleton preparations) and a direct effect on cancer cell proliferation mediated by the induction of apoptosis (unique to MCC). We have discovered that the immunomodulatory and apoptosis-inducing activities of MCC are due to the presence of DNA. Enzymatic degradation of DNA present in MCC with DNase I results in a significant reduction of the immunonodulatory and apoptosis-inducing activity, demonstrating that Mycobacterium phlei DNA plays a pivotal role in the activity of MCC. In addition, DNA purified from MCC or from Mycobacterium phlei was found to be able to induce cytokine synthesis and apoptosis of cancer cells. Studies to characterize sequences in Mycobacterium phlei DNA and MCC-associated DNA responsible for direct (apoptosis) and indirect (immunomodulation) anticancer activity has been performed. We have found that the activity of Mycobacterium phlei DNA is independent of the presence of unmethylated CpG motifs. In conclusion, we have demonstrated that the unique combination of chemotherapeutic-like (apoptosis) and immunotherapeutic (cytokine induction) activities of MCC is due to the presence of mycobacterial DNA.
Untitled 1
CSM-SCM Secretariat 17 Dossetter Way
Ottawa, ON K1G 4S3
Canada
