Molecular basis for resistance to erlotinib and development of agents that reverse the resistance

2013 Fiscal Year Final Research Report

• Project/Area Number: 23790189
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kagoshima University
• Principal Investigator: IKEDA Ryuji 鹿児島大学, 医学部・歯学部附属病院, 准教授 (50398278)
• Project Period (FY): 2011 – 2013
• Keywords: がん分子標的薬 / erlotinib / major vault protein / vault / PAK-104P

Research Abstract

Erlotinib, EGFR tyrosine kinase inhibitor, is an effective therapeutic agent for non-small cell lung cancer. However, inherent or acquired chemoresistance is known to be a major obstacle for anti-cancer therapies. I have isolated erlotinib resistant human non-small cell lung cancer A549 cells. PAK-104P inhibits the functions of p-gp, MRP1, MRP2 and Major vault protein (MVP). PAK-104P partially reversed the erlotinib resistance. It has been reported that the MVP mediates resistance to epidermal growth factor receptor-targeting agent such as erlotinib. I identified the crucial MVP promoter elements that regulate MVP expression. By deletion analysis, a conserved proximal E-box binding site was demonstrated to be important for human MVP promoter transactivation. Introduction of siRNA against USF 1 , which is known to bind the E-box binding site, decreased the expression of MVP. These findings suggest that USF1 binding to an E-box element may be critical for basal MVP promoter activation.

Research Products

• [Journal Article] Factors involved in the cisplatin resistance of KCP-4 human epidermoid carcinoma cells (2014)
  • Author(s): Oiso, S., Takayama, Y., Nakazaki, R., Matsunaga, N., Motooka, C., Yamamura, A., Ikeda, R., Nakamura, K., Takeda, Y., Kariyazono, H
  • Journal Title: Oncol. Rep Volume: 31 Pages: 719-726
  • Peer Reviewed
• [Journal Article] Regulation of Major Vault Protein Expression by Upstream Stimulating Factor 1 in SW620 Human Colon Cancer Cells, Oncol (2014)
  • Author(s): Ikeda, R., Nishizawa, Y., Tajitsu, Y., Minami, K., Mataki, H., Masuda, S., Furukawa, T., Akiyama, S., Yamada, K., Takeda, Y
  • Journal Title: Rep. Volume: 31 Pages: 197-201
  • Peer Reviewed
• [Journal Article] Antimicrobial effect of an ultrasonic levitation washer disinfector with silver electrolysis and ozone oxidation on methicillin-resistant Staphylococcus aureus (2013)
  • Author(s): Tamai, M., Matsushita, S., Miyanohara, H., Imuta, N., Ikeda, R., Kawai, K., Nishi, J., Sakamoto, A., Shigihara, T., Kanekura, T
  • Journal Title: J. Dermatol Volume: 40 Pages: 1020-1026
  • Peer Reviewed
• [Journal Article] Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma (2013)
  • Author(s): Shinsato, Y., Furukawa, T., Yunoue, S., Yonezawa, H., Minami, K., Nishizawa, Y., Ikeda, R., Kawahara, K., Yamamoto, M., Hirano, H., Tokimura, H., Arita, K
  • Journal Title: Oncotarget Volume: 4 Pages: 2261-2270
  • Peer Reviewed
• [Journal Article] Molecular basis for the expression of major vault protein induced by hyperosmotic stress in SW620 human colon cancer cells (2013)
  • Author(s): Tajitsu, Y., Ikeda, R., Nishizawa, Y., Mataki, H., Che, X.F., Sumizawa, T., Nitta, M., Yamaguchi, T., Yamamoto, M., Tabata, S., Akiyama, SI., Yamada, K., Furukawa, T., Takeda, Y
  • Journal Title: Int. J. Mol. Med Volume: 32 Pages: 703-708
  • Peer Reviewed
• [Journal Article] Molecular basis for the regulation of hypoxia-inducible factor-1αlevels by 2-deoxy-D-ribose (2013)
  • Author(s): Ikeda, R., Tabata, S., Tajitsu, Y., Nishizawa, Y., Minami, K., Furukawa, T., Yamamoto, M., Shinsato, Y., Akiyama, SI., Yamada, K, Takeda Y
  • Journal Title: Oncol. Rep Volume: 30 Pages: 1444-1448
  • Peer Reviewed
• [Journal Article] VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts (2013)
  • Author(s): Wang, J., Ikeda, R., Che, X.F., Ooyama, A., Yamamoto, M., Furukawa, T., Hasui, K., Zheng, C.L., Tajitsu, Y., Oka, T., Tabata, S., Nishizawa, Y., Eizuru, Y., Akiyama, SI
  • Journal Title: J. Oncol Volume: 43 Pages: 746-754
  • Peer Reviewed
• [Journal Article] Autocrine effects of neuromedin B stimulate the proliferation of rat primary osteoblasts (2013)
  • Author(s): Saito, H., Nakamachi, T., Inoue, K., Ikeda, R., Kitamura, K., Minamino, N., Shioda, S., Miyata, A
  • Journal Title: J. Endocrinol Volume: 217 Pages: 141-150
  • Peer Reviewed
• [Journal Article] Reichelderfer, M., Kolesar, J.M., Stability of infliximab in polyvinyl chloride bags (2012)
  • Author(s): Ikeda, R., Vermeulen, L.C., Lau, E., Jiang, Z., Saha, S
  • Journal Title: Am. J. Health Syst. Pharm Volume: 69 Pages: 1509-1512
  • Peer Reviewed
• [Journal Article] p53R2 is a prognostic factor of melanoma and regulates proliferation and chemosensitivity of melanoma cells (2012)
  • Author(s): Matsushita, S., Ikeda, R., Fukushige, T., Tajitsu, Y., Gunshin, K., Okumura, H., Ushiyama, M., Akiyama, S., Kawai, K., Takeda, Y., Yamada, K., Kanekura T
  • Journal Title: J. Dermatol. Sci Volume: 68 Pages: 19-24
  • Peer Reviewed
• [Journal Article] Analysis of the outcome of concurrent neoadjuvant chemoradiotherapy with S-1 compared to super-selective intra-arterial infusion for oral squamous cell carcinoma (2012)
  • Author(s): Miyawaki, A., Hijioka, H., Ikeda, R., Ishida, T., Nozoe, E., Nakamura, N
  • Journal Title: Oncol. Lett Volume: 3 Pages: 995-1001
  • Peer Reviewed
• [Journal Article] Neuromedin B stimulates proliferation of mouse chondrogenic cell line ATDC5 (2012)
  • Author(s): Saito, H., Ikeda, R., Inoue, K., Nagata, S., Kitamura, K., Minamino, N., Kangawa, K., Miyata, A
  • Journal Title: Peptides Volume: 36 Pages: 299-302
  • Peer Reviewed
• [Journal Article] Involvement of NF-κB activation in the cisplatin resistance of human epidermoid carcinoma KCP-4 cells, Oncol (2012)
  • Author(s): Oiso, S., Ikeda, R., Nakamura, K., Takeda, Y., Akiyama, S., Kariyazono, H
  • Journal Title: Rep Volume: 28 Pages: 27-32
  • Peer Reviewed
• [Journal Article] Thymidine phosphorylase activity is involved in augmented reactive oxygen species and interleukin-8 production in human cancer cells (2012)
  • Author(s): Tabata, S., Ikeda, R., Yamamoto, M., Furukawa, T., Kuramoto, T., Takeda, Y., Yamada, K., Haraguchi, M., Nishioka, Y., Sone, S., Akiyama, S
  • Journal Title: Oncol. Rep Volume: 28 Pages: 895-902
  • Peer Reviewed
• [Journal Article] Effect of 5-fluorouracil treatment on SN-38 absorption from intestine in rats (2011)
  • Author(s): Shibayama, Y., Iwashita, Y., Yoshikawa, Y., Kondo, T., Ikeda, R., Takeda, Y., Osada, T., Sugawara, M., Yamada, K., Iseki, K
  • Journal Title: Biol. Pharm. Bull Volume: 34 Pages: 1418-1425
  • Peer Reviewed
• [Journal Article] Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib (2011)
  • Author(s): S hibayama, Y., Nakano, K., Maeda, H., Taguchi, M., Ikeda, R., Sugawara, M., Iseki, K., Takeda, Y., Yamada, K
  • Journal Title: Biol. Pharm. Bull Volume: 34 Pages: 433-435
  • Peer Reviewed
• [Presentation] KB3-1細胞における5-aza-2-deoxycytidine (5-AZ)による5-fluorouracil(5-FU)の抗腫瘍効果増強作用 (2014)
  • Author(s): 西澤由紀彦、池田龍二、田實裕介、川原康一、山本雅達、新里能成、南謙太郎、古川龍彦、武田泰生
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台市
  • Year and Date: 20140000
• [Presentation] 処方監査手順書と抗がん剤チェックリストの導入によるがん化学療法監査均てん化への取り組み (2014)
  • Author(s): 有馬由佳、有馬純子、新田美奈、下堂薗権洋、池田龍二、武田泰生
  • Organizer: 日本臨床腫瘍薬学会学術大会2014
  • Place of Presentation: 千葉市
  • Year and Date: 20140000
• [Presentation] がん治療の最先端-基礎と臨床から-抗がん剤治療における現状と問題点 (2013)
  • Author(s): 池田龍二
  • Organizer: 第30回日本薬学会九州支部会
  • Place of Presentation: 長崎市
  • Year and Date: 20130000
• [Presentation] Molecular basis for regulation of hypoxia-inducible factor-1 alpha level by 2-deoxy-D-ribose (2013)
  • Author(s): Ikeda, R, Nishizawa, Y., Tajitsu, Y., Yamada, K., Takeda, Y
  • Organizer: 第7回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 仙台市
  • Year and Date: 20130000
• [Presentation] Vaultの高浸透圧耐性化機構 (2013)
  • Author(s): 池田龍二、西澤由紀彦、田實裕介、古川龍彦、山田勝士、武田泰生
  • Organizer: 第66回日本薬理学会西南部会
  • Place of Presentation: 福岡市
  • Year and Date: 20130000
• [Presentation] 高浸透圧で誘導されるヴォールトの発現亢進機序と高浸透圧耐性化機構 (2013)
  • Author(s): 池田龍二、田實裕介、西澤由紀彦、古川龍彦、秋山伸一、山田勝士、武田泰生
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡市
  • Year and Date: 20130000
• [Presentation] グリオーマの移動・浸潤におけるCaspr1の役割 (2012)
  • Author(s): 益田将吾、二川俊隆、山口沙織、山田勝士、池田龍二、武田泰生
  • Organizer: 第65回日本薬理学会西南部会
  • Place of Presentation: 熊本市
  • Year and Date: 20120000
• [Presentation] Molecular basis for the induction of vaults by anti-cancer agent and the role of vaults in resistance to anti-cancer agents (2012)
  • Author(s): Ikeda, R., Tajitsu, Y., Nishizawa, Y., Tominaga, N., Mataki, H., Yamada, K., Takeda, Y
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都市
  • Year and Date: 20120000
• [Presentation] 緑茶カテキンEpigallocatechin-3-gallate (EGCg)の抗がん特性 (2012)
  • Author(s): 本田修平、西原和也、園田純一郎、池田龍二、鳴海恵子、河内明夫、徳重恵利紗、武田泰生、本屋敏郎
  • Organizer: 第29回日本薬学会九州支部大会
  • Place of Presentation: 熊本市
  • Year and Date: 20120000
• [Presentation] A survey on communication skills for the trainees pharmaceutical practice (2012)
  • Author(s): Shimodozono, Y., Yaji, K., Ikeda, R., Takeda, Y
  • Organizer: 第22回日本医療薬学会年会
  • Place of Presentation: 新潟市
  • Year and Date: 20120000
• [Presentation] 手術部における薬剤師の取り組みと経済効果,医療薬学フォーラム2012 (2012)
  • Author(s): 有馬純子、佐藤史織、下堂薗権洋、池田龍二、武田泰生
  • Organizer: 第20回クリニカルファーマシーシンポジウム
  • Place of Presentation: 福岡市
  • Year and Date: 20120000
• [Presentation] チミジンホスホリラーゼ発現腫瘍での5-fluorouracil (5-FU)によるthrombospondin-1(TSP-1)発現誘導 (2011)
  • Author(s): 西澤由紀彦、池田龍二、田畑祥、田實裕介、俣木博徳、古川龍彦、牛山美奈、山口辰哉、山本雅達、松下茂人、秋山伸一、山田勝士、武田泰生
  • Organizer: 第64回日本薬理学会西南部会
  • Place of Presentation: 福岡市
  • Year and Date: 20110000
• [Presentation] 高浸透圧によるmajor vault protein (MVP)発現制御におけるSp1の役割 (2011)
  • Author(s): 田實裕介、池田龍二、田畑祥、西澤由紀彦、山口辰哉、牛山美奈、山本雅達、古川龍彦、秋山伸一、山田勝士、武田泰生
  • Organizer: 第64回日本薬理学会西南部会
  • Place of Presentation: 福岡市
  • Year and Date: 20110000
• [Presentation] Hyperosmotic stress up-regulates the expression of major vault protein in SW620 human colon cancer cells (2011)
  • Author(s): Ikeda, R., Tajitsu, Y., Nishizawa, Y., Tabata, S., Ushiyama, M., Furukawa, T., Akiyama, S., Yamada, K., Takeda, Y
  • Organizer: 第5回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 名古屋市
  • Year and Date: 20110000
• [Presentation] 抗がん剤耐性機序の解明に向けて (2011)
  • Author(s): 池田龍二、武田泰生、山田勝士
  • Organizer: 第5回日本緩和医療薬学会年会
  • Place of Presentation: 千葉市
  • Year and Date: 20110000
• [Book] 薬剤耐性Up-to-Date感染症・がん領域を中心にがん領域抗がん剤耐性機序の解明に向けて 月刊薬事 (2012)
  • Total Pages: 51-56