Combination of 13-Cis retinoic acid and lovastatin: marked antitumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice.
Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (S.N., A.Gi., Y.T., P.B., J.S., K.P.), National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology (S.N., K.Y., M.K.), William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Internal Medicine II (S.N., B.G., G.V.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, and Institute of Medical Informatics, Biometry, and Epidemiology (M.L.), University of Munich, Munich 81377, Germany; Department of Molecular Medicine (P.B.), Institute of Virology, Slovak Academy of Sciences, Bratislava 84505, Slovakia; Department of Internal Medicine III (J.S.), Nephrology, Rheumatology, and Endocrinology, Faculty of Medicine and Dentistry, Palacky University, Olomouc 77520, Czech Republic; Leidos Biomedical Research, Inc (M.A.), Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702; First Medical Department (S.F.), University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23538, Germany; and Oxford Centre for Diabetes, Endocrinology and Metabolism (A.Gr.), University of Oxford, Oxford OX3 7LE, United Kingdom.
Svenja
S
Nölting
Alessio
A
Giubellino
Yasin
Y
Tayem
Karen
K
Young
Michael
M
Lauseker
Petra
P
Bullova
Jan
J
Schovanek
Miriam
M
Anver
Stephanie
S
Fliedner
Márta
M
Korbonits
Burkhard
B
Göke
George
G
Vlotides
Ashley
A
Grossman
Karel
K
Pacak
D000199:Actins / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D015474:Isotretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009130:Muscle, Smooth / Q000737:chemistry; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000199:Actins; D018952:Antigens, CD34; D053379:Chromogranin A; D008148:Lovastatin; D014446:Tyrosine 3-Monooxygenase; D015474:Isotretinoin