The Anticancer Effects of Novel α-Bisabolol Derivatives Against Pancreatic Cancer.
Pancreatic cancer is highly malignant, characterized by aggressive proliferation, invasion, and metastasis. α-Bisabolol is an oily sesquiterpene alcohol derived from a variety of plants. We previously demonstrated that α-bisabolol is a potential therapeutic agent for pancreatic cancer. The aim of this study was to develop α-bisabolol derivatives which are more potent than the parent compound and may be clinically useful against pancreatic cancer. First, 22 derivatives of α-bisabolol were designed and synthesized. α-Bisabolol derivatives4and5had more potent inhibitory effects on the proliferation of pancreatic cancer cells than did α-bisabolol. Next, 15 additional α-bisabolol derivatives were designed and synthesized based on the structure of α-bisabolol derivatives4and5Among them, α-bisabolol derivative5had the strongest inhibitory effect on proliferation. This novel compound reduced the proliferation of various pancreatic cancer cell lines, such as KLM1, Panc1, and KP4. In addition, the compound induced higher levels of apoptosis in pancreatic cancer cell lines than did α-bisabolol. α-Bisabolol derivative5inhibited xenograft tumor growth and reduced dissemination of pancreatic cancer to peritoneal nodules. The compound strongly suppressed AKT expression in the peritoneal nodules. Reduced AKT expression in peritoneal nodules is consistent with an anticancer effect. These data indicate that α-bisabolol derivative5effectively prevents the progression of pancreatic cancer via inhibition of AKT. Taken together, the results showed that this compound has attractive therapeutic properties as a novel anticancer drug for pancreatic cancer.
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yoshihiko
Y
Murata
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan kokuryoh@med.nagoya-u.ac.jp.
Toshio
T
Kokuryo
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yukihiro
Y
Yokoyama
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Junpei
J
Yamaguchi
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tomohiro
T
Miwa
Department of Basic Medicinal Sciences, Nagoya University Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
Masatoshi
M
Shibuya
Department of Basic Medicinal Sciences, Nagoya University Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
Yoshihiko
Y
Yamamoto
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Masato
M
Nagino
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000032:analysis; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D000081222:Monocyclic Sesquiterpenes; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D000081222:Monocyclic Sesquiterpenes; D012717:Sesquiterpenes; C578959:carbohydrate antigen 199, human; C004497:bisabolol; D051057:Proto-Oncogene Proteins c-akt
AKT; apoptosis; pancreas cancer; peritoneal dissemination; α-Bisabolol derivatives