Research Projects

Support of projects regarding innovation of novel compounds in supportive and palliative care fields

We will offer and suggest adequate organization in NCC for innovation of novel compounds to improve QOL in cancer patients; novel analgesics, anti-emetics, compounds for improving cancer cachexia symptoms. Chief (Yasuhito Uezono) belongs to several organizations related to supportive and palliative care fields so that we will offer the best matching.

《Figure 1》

First-in-human, second and third clinical trials to develop a novel analgesic for oral mucositis in cancer patients

First-in-human trial and II/III clinical trials

(Supported by the Drug Discovery Support Promotion Project, Japan Agency for Medical Research and Development (AMED)）

1. Uezono Y, Miyano K, Sudo Y, Suzuki M, Shiraishi S, Terawaki K. A review of traditional Japanese medicines and their potential mechanism of action. Curr Pharm Des, 18:4839-4853, 2012. [PubMed]
2. Hitomi S, Ono K, Miyano K, Ota Y, Uezono Y, Matoba M, Kuramitsu S, Yamaguchi K, Matsuo K, Seta Y, Harano N, Inenaga K. Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats. J Neurosci Methods, 239:162-169, 2015. [PubMed]
3. Miyano K, Ueno T, Yatsuoka W, Uezono Y. Treatment for cancer patients with oral mucositis: assessment based on the Mucositis study group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and proposal of possible novel treatment with a Japanese herbal medicine. Curr Pharm Des, 22:2270-2278, 2016. [PubMed]
4. Yamaguchi K, Ono K, Hitomi S, Ito M, Nodai T, Goto T, Harano N, Watanabe S, Inoue H, Miyano K, Uezono Y, Matoba M, Inenaga K. Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil. Pain, 157:1004-1020, 2016. [PubMed]

Development of novel compounds for the inhibition of platelet-activating factor (PAF) signaling loop, the pathway causing progression of severe chronic pain

Innovation of novel compounds to inhibit the PAF-loop that causes chronic pain – seeds innovation

（Collaborative research with the Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, and supported by the Japan Agency for Medical Research and Development (AMED)）

1. Motoyama N, Morita K, Kitayama T, Shiraishi S, Uezono Y, Nishimura F, Kanematsu T, Dohi T. Pain-releasing action of platelet-activating factor (PAF) antagonists in neuropathic pain animal models and the mechanisms of action. Eur J Pain, 17:1156-1167, 2013. [PubMed]
2. Shindou H, Shiraishi S, Tokuoka SM, Takahashi Y, Harayama T, Abe T, Bando K, Miyano K, Kita Y, Uezono Y, Shimizu T. Relief from neuropathic pain by blocking of platelet-activating factor-pain loop. FASEB J, Epub ahead of print, 2017. [PubMed]

Development of novel and specific agonists for mu/delta opioid heterodimerized receptors

Innovation of novel opioid analgesics with less side effects – seeds innovation

（Collaborative research with Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, and supported by National Cancer Center Research and Development Fund）

1. Meguro Y, Miyano K, Hirayama S, Yoshida Y, Ishibashi N, Ogino T, Fujii Y, Manabe S, Eto M, Nonaka M, Fujii H, Ueta Y. Narita M, Sata N, Yada T, Uezono Y. Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator. J Pharmacol Sci, 137:67-75, 2018. (PMID: 29716811)
2. Imai S, Sudo Y, Nakamura A, Ozeki A, Asato M, Hojo M, Devi LA, Kuzumaki N, Suzuki T, Uezono Y, Narita M. Possible involvement of β-endorphin in a loss of the coordinated balance of μ-opioid receptors trafficking processes by fentanyl. Synapse, 65:962-966, 2011. [PubMed]
3. Narita M, Imai S, Nakamura A, Ozeki A, Asato M, Rahmadi M, Sudo Y, Hojo M, Uezono Y, Devi LA, Kuzumaki N, Suzuki T. Possible involvement of prolonging spinal µ-opioid receptor desensitization in the development of antihyperalgesic tolerance to µ-opioids under a neuropathic pain-like state. Addict Biol, 18:614-622, 2013. [PubMed]
4. Miyano K, Sudo Y, Yokoyama A, Hisaoka-Nakashima K, Morioka N, Takebayashi M, Nakata Y, Higami Y, Uezono Y. History of the G protein-coupled receptor (GPCR) assays from traditional to a state-of-the-art biosensor assay. J Pharmacol Sci, 126:302-309, 2014. [PubMed]
5. Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, Yamamoto M, Warabi E, Sudo Y, Yokoyama A, Miyano K, Hirokawa T, Uezono Y. Ignavine: orthosteric enhancer of the μ opioid receptor. Sci Rep, 6:31748, 2016. [PubMed]  

Development of compounds for the improvement of cancer cachexic symptoms: clinical application of ghrelin and des-acyl ghrelin for the inhibition of cardiac intoxication from chemotherapy and/or cancer cachexia

•  Development of ghrelin and des-acyl ghrelin as novel compounds for improvement of symptoms of cancer cachexia –translational research to the I, II, III clinical trial
• Identification of a novel des-acyl ghrelin receptor yet cloned in collaboration with National Cerebral and Cardiovascular Center and Kagoshima University, supported by National Cancer Center Research and Development Fund

1. Nonaka M, Kurebayashi N, Murayama T, Sugihara M, Terawaki K, Shiraishi S, Miyano K, Hosoda H, Kishida S, Kangawa K, Sakurai T, Uezono Y. Therapeutic potential of ghrelin and des-acyl ghrelin against chemotherapy-induced cardiotoxicity. Endocr J, 64 (Suppl):S35-S39, 2017. (PMID: 28652542)
2. Terawaki K, Sawada Y, Kashiwase Y, Hashimoto H, Yoshimura M, Suzuki M, Miyano K, Sudo Y, Shiraishi S, Higami Y, Yanagihara K, Kase Y, Ueta Y, Uezono Y. New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line. Am J Physiol Endocrinol Metab, 306:E373-387, 2014. [PubMed]
3. Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N, Takeda H, Asaka M, Inui A. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol Psychiatry, 21:1613-1623, 2016. [PubMed]
4. Tagami K, Kashiwase Y, Yokoyama A, Nishimura H, Miyano K, Suzuki M, Shiraishi S, Matoba M, Ohe Y, Uezono Y. The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: an in vitro study with cells expressing cloned human growth hormone secretagogue receptor. Neuropeptides, 58:93-101, 2016. [PubMed]
5. Terawaki K, Kashiwase Y, Sawada Y, Hashimoto H, Yoshimura M, Ohbuchi K, Sudo Y, Suzuki M, Miyano K, Shiraishi S, Higami Y, Yanagihara K, Hattori T, Kase Y, Ueta Y, Uezono Y. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the kampo medicine rikkunshito on the model. PLoS One, 12:e0173113, 2017. [PubMed]
6. Ohnishi S, Watari H, Kanno M, Ohba Y, Takeuchi S, Miyaji T, Oyamada S, Nomura E, Kato H, Sugiyama T, Asaka M, Sakuragi N, Yamaguchi T, Iwase S, Uezono Y. Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02). J Gynecol Oncol, 28:e44, 2017. (PMID: 28657216)

Research of Japanese kampo medicines to improve QOL in cancer patients

Research of kampo medicines as repositioning drugs based on basic research of kampo medicines to reduce side effects by chemotherapy.

1. Sakai H, Tabata S, Kimura M, Yabe S, Isa Y, Kai Y, Sato F, Yumoto T, Miyano K, Narita M, Uezono Y. Active Ingredients ingredients of hange-shashin-to, baicalelin and 6-gingerol, inhibit 5-fluorouracil-induced upregulation of CXCL1 of in the colon to attenuate diarrhea development. Biol Pharm Bull, 40:2134-2139, 2017. (PMID: 29199237)
2. Terawaki K, Kashiwase Y, Sawada Y, Hashimoto H, Yoshimura M, Ohbuchi K, Sudo Y, Suzuki M, Miyano K, Shiraishi S, Higami Y, Yanagihara K, Hattori T, Kase Y, Ueta Y, Uezono Y. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the kampo medicine rikkunshito on the model. PLoS One, 12:e0173113, 2017. (PMID: 28249026)
3. Ohnishi S, Watari H, Kanno M, Ohba Y, Takeuchi S, Miyaji T, Oyamada S, Nomura E, Kato H, Sugiyama T, Asaka M, Sakuragi N, Yamaguchi T, Iwase S, Uezono Y. Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02). J Gynecol Oncol, 28:e44, 2017. (PMID: 28657216)
4. Miyano K, Ueno T, Yatsuoka W, Uezono Y. Treatment for cancer patients with oral mucositis: assessment based on the Mucositis study group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and proposal of possible novel treatment with a Japanese herbal medicine. Curr Pharm Des, 22:2270-2278, 2016. (PMID: 26891806)
5. Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, Yamamoto M, Warabi E, Sudo Y, Yokoyama A, Miyano K, Hirokawa T, Uezono Y. Ignavine: orthosteric enhancer of the ? opioid receptor. Sci Rep, 6:31748, 2016. (PMID: 27530869)
6. Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N, Takeda H, Asaka M, Inui A. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol Psychiatry, 21:1613-1623, 2016. (PMID: 26830139)
7. Terawaki K, Sawada Y, Kashiwase Y, Hashimoto H, Yoshimura M, Suzuki M, Miyano K, Sudo Y, Shiraishi S, Higami Y, Yanagihara K, Kase Y, Ueta Y, Uezono Y. New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line. Am J Physiol Endocrinol Metab, 306:E373-387, 2014. (PMID: 24347053)
8. Uezono Y, Miyano K, Sudo Y, Suzuki M, Shiraishi S, Terawaki K. A review of traditional Japanese medicines and their potential mechanism of action. Curr Pharm Des, 18:4839-4853, 2012. (PMID: 22632864)