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(caption on next page)
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 Haloperidol in the serum of mice after 14 days. AST, aspartate aminotransferase; GGT, γ-glutamyl transpeptidase; ALT, alanine aminotransferase.
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.
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
Anti-cancer Effects of a Chemically Modified miR-143 on Bladder Cancer
by Either Systemic or Intravesical Treatment
Yuki Yoshikawa,1,2 Kohei Taniguchi,3 Takuya Tsujino,1,2 Kazuki Heishima,1 Teruo Inamoto,2 Tomoaki Takai,1,2 Koichiro Minami,1,2 Haruhito Azuma,2 Kanjiro Miyata,4 Kotaro Hayashi,5 Kazunori Kataoka,5,6 and Yukihiro Akao1
1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; 2Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan; 3Translational Research Program, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan; 4Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; 5Inovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; 6Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
We developed a novel chemically modified miR-143 (miR-143#12), and with it we investigated the contribution of miR-143 to the pathogenesis of bladder cancer (BC), in which miR-143 is extremely downregulated. Since miR-143 silenced K-RAS and RAS effector-signaling molecules Erk and Akt, we performed the ectopic expression of miR-143 in human BC 253J-BV cells, and we examined the growth inhibition and the mechanism of it in vitro and in orthotopic model mice. As a result, miR-143#12 induced a marked growth inhibition with apoptosis through impairing RAS-signaling networks, including SOS1, which exchanges guanosine diphosphate (GDP)/RAS for active guanosine triphosphate (GTP)/RAS. In the in vivo study, miR-143#12 exhibited a marked anti-tumor activity by either systemic or intravesical administration with polyionic copolymer (PIC) as the carrier, compared with the ac-tivity obtained by use of lipofection. These findings raised the possibility that the chemically modified miR-143#12 would be a candidate of microRNA (miRNA) medicine for BC deliv-ered by intravesical infusion.
Bladder cancer (BC) is one of the most common cancers of the uro-genital system. Over 20,000 new cases of BC were identified in Japan in 2015, and approximately over 8,000 deaths from BC were antici-pated. BC can be classified into 2 types, i.e., muscle-invasive BC (MIBC) and non-muscle-invasive BC (NMIBC). NMIBC can be managed with transurethral resection of the bladder tumor and intra-vesical chemotherapy and/or immunotherapy.1 Compared with NMIBC, MIBC is a highly aggressive disease. For patients with NMIBC, the issue is to prevent tumor recurrence, which occurs in 50%–90% of the patients within 5 years, and, most importantly, dis-ease progression to muscle invasion, which occurs in up to 20% of pa-tients.2 In particular, carcinoma in situ (CIS) is regarded as a problem. It is classified as NMIBC, but its recurrence rate is as high as 90% and treatment for it, bladder preservation, is ineffective. On the other hand, patients who are diagnosed as having MIBC also have an unfa-
vorable prognosis, with a 5-year overall and cancer-specific survival period estimated to be approximately 60% because of no effective drug.3,4 Thus, there is a need to identify the driver genes and to develop a more effective therapeutic strategy for BC.