PMID- 27181081
OWN - NLM
STAT- MEDLINE
DCOM- 20170201
LR  - 20181202
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 39
IP  - 8
DP  - 2016 Aug 1
TI  - Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human 
      Pancreatic Cancer Cell Lines: An in Vitro Study.
PG  - 1238-46
LID - 10.1248/bpb.b15-00746 [doi]
AB  - Bisphosphonates and statins are known to have antitumor activities against 
      different types of cancer cell lines. In the present study, we investigated the 
      antiproliferative effects of the combination of zoledronic acid (ZOL), a 
      bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of 
      human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer 
      cell lines were treated with ZOL and FLU both individually and in combination to 
      evaluate their antiproliferative effects using WST-8 cell proliferation assay. In 
      this study, we demonstrated a potent synergistic antiproliferative effect of both 
      drugs when used in combination in both cell lines. Moreover, we studied the 
      molecular mechanism behind this synergistic effect, which was inhibited by the 
      addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and 
      geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the 
      effect of ZOL and FLU combination on RhoA and Ras guanosine 5'-triphosphate 
      (GTP)-proteins. The combination induced a marked accumulation in RhoA and 
      unprenylated Ras. GGPP and FPP reversed the increase in the amount of both 
      proteins. These results indicated that the combination treatment impaired RhoA 
      and Ras signaling pathway by the inhibition of geranylgeranylation and/or 
      farnesylation. This study provides a potentially effective approach for the 
      treatment of pancreatic cancer using a combination treatment of ZOL and FLU.
FAU - Elsayed, Mahitab
AU  - Elsayed M
AD  - Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of 
      Pharmaceutical Sciences, Kyushu University.
FAU - Kobayashi, Daisuke
AU  - Kobayashi D
FAU - Kubota, Toshio
AU  - Kubota T
FAU - Matsunaga, Naoya
AU  - Matsunaga N
FAU - Murata, Ryusei
AU  - Murata R
FAU - Yoshizawa, Yuko
AU  - Yoshizawa Y
FAU - Watanabe, Natsuki
AU  - Watanabe N
FAU - Matsuura, Tohru
AU  - Matsuura T
FAU - Tsurudome, Yuya
AU  - Tsurudome Y
FAU - Ogino, Takashi
AU  - Ogino T
FAU - Ohdo, Shigehiro
AU  - Ohdo S
FAU - Shimazoe, Takao
AU  - Shimazoe T
LA  - eng
PT  - Journal Article
DEP - 20160514
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Diphosphonates)
RN  - 0 (Fatty Acids, Monounsaturated)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Polyisoprenyl Phosphates)
RN  - 124671-05-2 (RHOA protein, human)
RN  - 4L066368AS (Fluvastatin)
RN  - 6XC1PAD3KF (Zoledronic Acid)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
RN  - N21T0D88LX (geranylgeranyl pyrophosphate)
RN  - S5UOB36OCZ (Mevalonic Acid)
SB  - IM
MH  - Anticholesteremic Agents/pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Antioxidants/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Diphosphonates/*pharmacology
MH  - Fatty Acids, Monounsaturated/*pharmacology
MH  - Fluvastatin
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Indoles/*pharmacology
MH  - Mevalonic Acid/metabolism
MH  - Pancreatic Neoplasms/metabolism
MH  - Polyisoprenyl Phosphates/metabolism
MH  - Zoledronic Acid
MH  - ras Proteins/metabolism
MH  - rhoA GTP-Binding Protein/metabolism
EDAT- 2016/05/18 06:00
MHDA- 2017/02/02 06:00
CRDT- 2016/05/17 06:00
PHST- 2016/05/17 06:00 [entrez]
PHST- 2016/05/18 06:00 [pubmed]
PHST- 2017/02/02 06:00 [medline]
AID - 10.1248/bpb.b15-00746 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2016 Aug 1;39(8):1238-46. doi: 10.1248/bpb.b15-00746. Epub 2016 
      May 14.