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WITHDRAWN: Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells
Accepted Manuscript Title: Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells Author: Yuki Yamashita, Nao Tanaka, Risako Onodera, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima PII: DOI: Reference:
S1818-0876(15)00242-1 http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.079 AJPS 304
To appear in:
Asian Journal of Pharmaceutical Sciences
Please cite this article as: Yuki Yamashita, Nao Tanaka, Risako Onodera, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells, Asian Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.079. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells Yuki Yamashitaa, Nao Tanakaa, Risako Onoderaa, Keiichi Motoyamaa, Taishi Higashia, Hidetoshi Arimaa,b,* a
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-
ku, Kumamoto, Japan b
Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and
Glocal Oriented) Program”, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Japan *E-mail: [email protected] In cancer chemotherapy to obtain the maximum treatment efficacy of anticancer agents, the drugdelivery technique is extremely important. Recently, folic acid (FA) has emerged as a prominent tumor targeting moiety capable of specific interaction with tumor cells expressing the folate receptor-α (FR-α).Notably, Grosse et al. reported that the intraperitoneal administration of methyl-β -cyclodextrin (M-β-CyD) had antitumor activity in tumor bearing mice [1].However, the cytotoxic reaction of M- β -CyD has a lack ofa tumor cellselectivity. Therefore, to confer tumor cell-selective cytotoxicityonmethyl-β-cyclodextrin (M-β-CyD),we previously synthesized folate-appended M-β-CyD (FA-M-β-CyD), and revealed itsantitumor activity in mice inoculated with Colon-26 cells, a murine colon carcinoma cell line [2]. In the present study, to examine the antitumor activity of FA-M-β-CyD in “FR-α-expressing human tumor models”, we performed in vivo antitumor experiments in KB cells (FR-α positive)-xenografted BALB/c nude mice. As the results, FA-M-β-CyD drastically inhibited the tumor growth after intravenous injection to KB cells-xenografted mice. In addition, this antitumor activity of FA-M-β-CyD was superior to that of doxorubicin after an intravenous administration at the same dose. Importantly, an intravenous administration of FA-M-βCyD to KB cells-xenografted mice showed the only slight change in blood chemistry values. To gain insight into the antitumor mechanism of FA-M-β-CyD, we performed the in vitro study using KB cells (FR-α positive). Notably, FR-α-overexpressing cell-selective cytotoxic activity of FA-M-β-CyD was found to be mediated by the induction of autophagy, because of the enhancement of autophagy marker expression such as LC3-II and beclin-1 [3].The induction of autophagy by FA-M-β-CyD was associated with mitochondrial dysfunction such as reactive oxygen species (ROS) generation and ATP production. Raman microscopic analysis also revealed the mitochondrial dysfunction because FA-M-β-CyD changed Raman signals derived from the mitochondrial domain in KB cells. Collectively, these results strongly suggest that FA-M-β-CyD has the potential as a promising anticancer agentassociated with autophagyfor “FR-α-expressing human solid tumor cells”.
Page 1 of 2
Keywords: Cancer; Folate receptor; Autophagy; Mitochondria; Methyl-β-cyclodextrin
Acknowledgements The authors acknowledge the financial supports received from Center for Clinical and Translational Research of Kyushu University Hospital.
References [1] Grosse PY, Bressolle F, Pinquet F. Antiproliferative effect of methyl-β-cyclodextrin in vitro and in human tumour xenografted athymic nude mice. Brit J Cancer 1998; 78:1165-1169. [2] Onodera R,Motoyama K, Okamatsu A,et al. Potential use of folate-appended methyl-β-cyclodextrin as an anticancer agent. Sci Rep 2013; 3:1-9. [3] Onodera R, Motoyama K, Tanaka N, et al. Involvement of autophagy in antitumor activity of folateappended methyl-β-cyclodextrin.Sci Rep2014; 4:1-8.
Fig. 1. Effects of FA-M-β-CyD on Tumor Growth (A, B) inKB cells (FR-α (+))-xenografted miceafter Intravenous AdministrationEach point represents the mean±S.E. of 4-5 experiments. *p< 0.05, compared with control (5% mannitol solution).†p< 0.05, compared with DOX.‡p< 0.05, compared with M-β-CyD.
Page 2 of 2
S1818-0876(15)00242-1 http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.079 AJPS 304
To appear in:
Asian Journal of Pharmaceutical Sciences
Please cite this article as: Yuki Yamashita, Nao Tanaka, Risako Onodera, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells, Asian Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.079. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Antitumor activity of folate-appended methyl-β-cyclodextrin in mice xenografted human solid tumor cells Yuki Yamashitaa, Nao Tanakaa, Risako Onoderaa, Keiichi Motoyamaa, Taishi Higashia, Hidetoshi Arimaa,b,* a
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-
ku, Kumamoto, Japan b
Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and
Glocal Oriented) Program”, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Japan *E-mail: [email protected] In cancer chemotherapy to obtain the maximum treatment efficacy of anticancer agents, the drugdelivery technique is extremely important. Recently, folic acid (FA) has emerged as a prominent tumor targeting moiety capable of specific interaction with tumor cells expressing the folate receptor-α (FR-α).Notably, Grosse et al. reported that the intraperitoneal administration of methyl-β -cyclodextrin (M-β-CyD) had antitumor activity in tumor bearing mice [1].However, the cytotoxic reaction of M- β -CyD has a lack ofa tumor cellselectivity. Therefore, to confer tumor cell-selective cytotoxicityonmethyl-β-cyclodextrin (M-β-CyD),we previously synthesized folate-appended M-β-CyD (FA-M-β-CyD), and revealed itsantitumor activity in mice inoculated with Colon-26 cells, a murine colon carcinoma cell line [2]. In the present study, to examine the antitumor activity of FA-M-β-CyD in “FR-α-expressing human tumor models”, we performed in vivo antitumor experiments in KB cells (FR-α positive)-xenografted BALB/c nude mice. As the results, FA-M-β-CyD drastically inhibited the tumor growth after intravenous injection to KB cells-xenografted mice. In addition, this antitumor activity of FA-M-β-CyD was superior to that of doxorubicin after an intravenous administration at the same dose. Importantly, an intravenous administration of FA-M-βCyD to KB cells-xenografted mice showed the only slight change in blood chemistry values. To gain insight into the antitumor mechanism of FA-M-β-CyD, we performed the in vitro study using KB cells (FR-α positive). Notably, FR-α-overexpressing cell-selective cytotoxic activity of FA-M-β-CyD was found to be mediated by the induction of autophagy, because of the enhancement of autophagy marker expression such as LC3-II and beclin-1 [3].The induction of autophagy by FA-M-β-CyD was associated with mitochondrial dysfunction such as reactive oxygen species (ROS) generation and ATP production. Raman microscopic analysis also revealed the mitochondrial dysfunction because FA-M-β-CyD changed Raman signals derived from the mitochondrial domain in KB cells. Collectively, these results strongly suggest that FA-M-β-CyD has the potential as a promising anticancer agentassociated with autophagyfor “FR-α-expressing human solid tumor cells”.
Page 1 of 2
Keywords: Cancer; Folate receptor; Autophagy; Mitochondria; Methyl-β-cyclodextrin
Acknowledgements The authors acknowledge the financial supports received from Center for Clinical and Translational Research of Kyushu University Hospital.
References [1] Grosse PY, Bressolle F, Pinquet F. Antiproliferative effect of methyl-β-cyclodextrin in vitro and in human tumour xenografted athymic nude mice. Brit J Cancer 1998; 78:1165-1169. [2] Onodera R,Motoyama K, Okamatsu A,et al. Potential use of folate-appended methyl-β-cyclodextrin as an anticancer agent. Sci Rep 2013; 3:1-9. [3] Onodera R, Motoyama K, Tanaka N, et al. Involvement of autophagy in antitumor activity of folateappended methyl-β-cyclodextrin.Sci Rep2014; 4:1-8.
Fig. 1. Effects of FA-M-β-CyD on Tumor Growth (A, B) inKB cells (FR-α (+))-xenografted miceafter Intravenous AdministrationEach point represents the mean±S.E. of 4-5 experiments. *p< 0.05, compared with control (5% mannitol solution).†p< 0.05, compared with DOX.‡p< 0.05, compared with M-β-CyD.
Page 2 of 2