Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer.
OBJECTIVE
Pancreatic cancer is a highly aggressive malignancy, and improvement in systemic therapy is necessary to treat this frequently encountered metastatic disease. The current targeted agents used in combination with gemcitabine improved objective response rates, but with little or no improvements in survival and also increased toxicities in pancreatic cancer patients. Recently, we showed that the triterpenoid cucurbitacin B inhibited tumour growth in pancreatic cancer cells by inhibition of the JAK/STAT pathway, and synergistically increased antiproliferative effects of gemcitabine in vitro.


METHODS
The anti-tumour effects and toxicities of cucurbitacin B in combination with gemcitabine were tested against human pancreatic cancer cells in a murine xenograft model.


RESULTS
Combined therapy with cucurbitacin B and gemcitabine at relatively low doses (0.5 mg x kg(-1) and 25 mg x kg(-1) respectively) resulted in highly significant tumour growth inhibition of pancreatic cancer xenografts (up to 79%). Remarkably, this therapy was well tolerated by the animals, as shown by histology of visceral organs, analysis of serum chemistry, full blood counts and bone marrow colony numbers. Western blot analysis of the tumour samples of mice who received both cucurbitacin B and gemcitabine, revealed stronger inhibition of Bcl-XL, Bcl-2 and c-myc, and higher activation of the caspase cascades, than mice treated with either agent alone.


CONCLUSIONS
Combination of cucurbitacin B and gemcitabine had profound anti-proliferative effects in vivo against xenografts of human pancreatic cancer cells, without any significant signs of toxicity. This promising combination should be examined in therapeutic trials of pancreatic cancer.
Iwanski
Gabriela B
GB
Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. gabriela.iwanski@cshs.org
Lee
Dhong H
DH
En-Gal
Shlomit
S
Doan
Ngan B
NB
Castor
Brandon
B
Vogt
Marco
M
Toh
Melvin
M
Bokemeyer
Carsten
C
Said
Jonathan W
JW
Thoennissen
Nils H
NH
Koeffler
H Phillip
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014315:Triterpenes; C041246:cucurbitacin B; D003841:Deoxycytidine; D000093542:Gemcitabine