Abstract
A handful of monoclonal antibodies have recently been introduced in treatment of hematopoietic malignant neoplasms and solid tumors. The complement system, an important arm of the immune system, is activated following anti-tumor antibody treatment. Complement proteins assemble to form channel-like pores called MAC (Membrane Attack Complexes) that inflict damage to target cells. Unfortunately, cancer cells have many defensive strategies against antibody-dependent complement-mediated cytotoxicity, including MAC shedding by exocytosis. Our recent results have implicated mortalin, the mitochondrial heat shock protein 70, in the removal of the MAC from the cell surface. Mortalin is known to have tumor promoting and anti-apoptotic effects. Our research hypothesis states that mortalin is a vital protector of tumor cells from immune damage. In order to examine this hypothesis, we set up two mouse models of cancer, of K562 erythroleukemia cells in nude mice and EL4 T-lymphoma cells in C57BL/6 mice. Mortalin siRNA was administered to tumor bearing mice with or without concomitant tumor directed antibodies. First, in vitro experiments showed that mortalin siRNA acts synergistically with anti-cancer antibodies in lysis of tumor cells. In vitro mortalin silencing in tumor cells by siRNA and then injection of the cells into mice demonstrated reduced tumor growth, relative to cells pretreated with scrambled siRNA. Mortalin silencing in vivo by intratumoral or intravenous injection of mortalin siRNA led to a significant decrease in tumor growth rate. Furthermore, mortalin siRNA also reduced tumor blood supply and caused tumor necrosis. Growth rate of EL4 and K562 tumors was also significantly inhibited by injection of the mortalin inhibitor MKT‐077. Mortalin inhibition in tumors may thus be regarded as a novel adjuvant treatment to immunotherapy.
Citation Information: Cancer Res 2009;69(23 Suppl):B38.
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