Vanilloids in pancreatic cancer: potential for chemotherapy and pain management.
BACKGROUND
Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients.


METHODS
In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells--either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine--was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristics--especially pain levels--were registered in a prospective database and correlated with VR1 expression.


RESULTS
Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis.


CONCLUSIONS
Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.
Hartel
M
M
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
di Mola
F F
FF
Selvaggi
F
F
Mascetta
G
G
Wente
M N
MN
Felix
K
K
Giese
N A
NA
Hinz
U
U
Di Sebastiano
P
P
Büchler
M W
MW
Friess
H
H
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002908:Chronic Disease; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004224:Diterpenes / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress; D010146:Pain / Q000517:prevention & control*; D010179:Pancreas / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000150:complications / Q000188:drug therapy*; D010195:Pancreatitis / Q000188:drug therapy; D011446:Prospective Studies; D050916:TRPV Cation Channels / Q000032:analysis; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004224:Diterpenes; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D003841:Deoxycytidine; C024353:resiniferatoxin; D005472:Fluorouracil; D000093542:Gemcitabine