Abstract
Management of advanced colorectal cancer is challenging due to the lack of efficient therapy. The lipid A, OM-174 exhibited antitumor activity in colorectal cancer. We explored the anticancer efficacy of this compound in rats bearing large colorectal tumors in combination with the platinum derivative drugs oxaliplatin and cisplatin. While each drug used alone exhibited partial antitumor activity, sequential treatment with oxaliplatin or cisplatin for one week followed by lipid A injections induced a great regression of colorectal tumors, with more than 95% of rats cured from their tumors. This potent antitumor efficacy of the combined treatments was correlated to the sequential induction of cellular senescence by oxaliplatin, and of apoptosis, mainly triggered by the lipid A. Moreover, a recruitment of tumor-associated neutrophils with N1 phenotype as attested by the expression of inducible nitric oxide synthase was observed with combination of oxaliplatin and lipid A. Neutrophil recruitment within tumor microenvironment was due to oxaliplatin and lipid A-dependent release of neutrophil specific chemoattractants such as cxcl1 and 2. However the N1 phenotype is only dependent of lipid A treatment. These results suggest that the combination of chemotherapy with an immunotherapy is a promising approach to treat patients with advanced colorectal cancer.
Highlights
Colorectal cancer is the second leading cause of death in Northern countries [1]
Lipid A induced apoptosis of cancer cells which was increased by oxaliplatin We have explored the mechanisms involved in the antitumor efficacy of platinum derivative/lipid A combination
The life span of rats bearing large nodules of colon cancer was greatly increased when animals were treated with the platinum derivative drugs cisplatin or oxaliplatin, together with an analog of lipid A
Summary
Despite significant developments in the treatment of this disease by using new cytotoxic chemotherapies and novel biological agents, it still causes considerable mortality in patients with metastatic colorectal cancer (mCRC) [2]. The antitumor efficacy of these drugs has been ascribed to their ability to block the growth of tumors through different mechanisms. They can induce apoptosis of tumor cells by the activation of series of cysteine proteases called caspases [4] or their senescence, a process leading to irreversible arrest of cell division. The activation of any of these senescence pathways triggers a permanent arrest of growth of transformed cells and prevents carcinogenesis. Even though senescent cells cannot proliferate they are still metabolically active and release a broad variety of cytokines and chemokines that modify the microenvironment
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