br knockdown of p did not completely eliminate the

knockdown of p65 did not completely eliminate the transcription of IL-1α and IL-1β, indicating that Mar-C is a selective SASP modulator. Although the involvement of other transcriptional factors or mechan-isms remain further investigation in Mar-C-mediated regulation of SASP, the interventions of pro-inflammatory SASP by Mar-C would al-leviate the deleterious effects of SASP accompanied with the growth inhibition of tumors.
In addition, induction of apoptosis of senescent L-NAME or enhanced immune clearance is also a promising strategy to alleviate the dele-terious effects of SASP in response to chemical agents [46–48]. Curdlan sulfate (CS), a soluble sulfated derivative of curdlan which is an ex-tracellular polysaccharide of bacteria origin, possesses immunological adjuvant properties. Studies on CS had shown that it had im-munopotentiating activity, including activating macrophages, bone marrow derived dendritic cell (BMDC) maturation and inducing sple-nocyte proliferation [15,49,50]. The combination of Mar-C and CS
indeed exhibited anti-tumor effect on tumor-bearing mice without toxicity, though without significant difference between Mar-C and Mar-C + CS. As our first investigation on the combination of Mar-C and CS, it did show a synergistic tendency. These results paced a way for further optimization of combined Mar-C with CS in cancer treatment. More-over, whether Mar-C has immunomodulating activity and if Mar-C has synergistic anti-tumor action when it is used with other im-munomodulators still remain further investigation.
In summary, our results revealed a novel anti-tumor mechanism of Mar-C, selectively promoting cancer cell senescence but with limited cytotoxicity for normal cells and predominantly extending the survival of the tumor-bearing mice. The distinct modulation on SASP by Mar-C may also provide substantial benefits for cancer therapy. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.bbagen.2019.05.006.
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Fig. 6. Antitumor activity of Mar-C in combination with immunomodulator curdlan sulfate in vivo. (A) Image of primary lewis lung carcinoma (LLC) cell tumors after treatment with vehicle, DOX, Mar-C, curdlan sulfate (CS) and Mar-C plus CS for 14 days. (B) The weight of primary tumor after treatment for 14 days in different groups. (C) Immunohistochemical staining of Ki-67 in vehicle, Mar-C and Mar-C plus CS-treated groups of LLC homografts. (D) Changes in body weight of LLC tumor-bearing mice for 14 days. (E) The splenic index of tumor-bearing mice after treatment. (F) Liver function assays. Changes of liver enzymes in the serum of mice after 14 days. AST, aspartate aminotransferase; GGT, γ-glutamyl transpeptidase; ALT, alanine aminotransferase.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China NO. 81473238 and 81872896, by Shandong Key Innovative Research Program NO. 2018CXGC1216.
Conflicts of interest
The authors disclose no conflicts of interest.
References
S. Fayyaz, C.W. Shu, H.W. Chang, Oxidative stress-modulating drugs have pre-ferential anticancer effects - involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration, Semin. Cancer Biol. (2018) (In press).
C. Cordon-Cardo, S.W. Lowe, Senescence and tumour clearance is triggered by p53  BBA - General Subjects xxx (xxxx) xxx–xxx
15 Original Article
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