Abstract
Chemotherapy and immunotherapy are the main remedies used in cancer treatment. Because immunotherapy can not only reduce the toxicity of chemotherapeutics but also enhance antitumor effects in vivo, combining these two therapies is a trend that continues to gain more attention in clinic. SEP, a polysaccharide isolated from Strongylocentrotus nudus egg, has been reported to display antitumor activity by stimulating immune cells, including NK and T cells, via TLR2 and TLR4. In the present study, the synergistic effect between SEP and 5-fluorouracil (5-FU), a traditional cytotoxic drug, in vitro and in vivo was investigated. The results obtained indicated that SEP alone stimulated NK-92 cytotoxicity and coordinated with 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells in vitro. SEP promoted NK-92 activity by stimulating NKG2D and its downstream DAP10/PI3K/Erk signaling pathway. Additionally, 5-FU could increase MICA expression on HepG-2 or A549 cells and prevent membrane MICA from shedding as soluble MICA, which were abrogated in the tumor cells transfected with ADAM 10 overexpression plasmid. Moreover, in H22- or Lewis lung cancer (LLC)-bearing mouse models, SEP reversed 5-FU-induced atrophy and apoptosis in both the spleen and bone marrow in vivo by suppressing ROS generation and caspase-3 activation. All of these results highlight the potential for the combination of SEP and 5-FU in cancer therapy in the future.
Highlights
Cytotoxic chemotherapy is an effective treatment for cancer
We measured the potential of Strongylocentrotus nudus eggs polysaccharide (SEP) and 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells
Co-culture of NK-92 cells pretreated with SEP (200 μg/mL, 24 h) and HepG-2 or A549 cells pretreated with 5-FU (20 μg/mL, 24 h) resulted in significantly enhanced NK cytotoxicity against both cancer cell lines (Figure 1C and 1D)
Summary
Cytotoxic chemotherapy is an effective treatment for cancer. using cytotoxic agents exhibited toxicities towards normal tissues, including the development of hematopoietic and immune suppression, and led to the occurrence of drug-resistant tumor cells [1, 2]. On the other hand, based on the immune effects of chemotherapy drugs, synergy between chemotherapy and immunotherapy has been seen in several clinical trails; for example, an obvious outcome of gemcitabine combined with IL-2 treatment was observed in patients with metastatic colorectal cancer [5, 6]. In these studies, chemotherapy was found to be immunomodulatory, enhance the crosswww.impactjournals.com/oncotarget presentation of tumor antigens, and make cytotoxic CTL/NK cells more susceptible to tumor cells despite their immunosuppressive effects [5,6,7]
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