TY - JOUR
T1 - 5′-methylschweinfurthin G reduces chondrosarcoma tumor growth
AU - Stevens, Jeff W.
AU - Meyerholz, David K.
AU - Neighbors, Jeffery D.
AU - Morcuende, José A.
N1 - Funding Information:
Terpenoid Therapeutics Incorporated (Coralville, IA) for donation of the schweinfurthin compound, TTI-3144 (The University of Iowa, Division of Sponsored Programs, Uniform Biological Material Transfer Agreement reference #: N2013090025). Drs. Raymond J. Hohl, David F. Wiemer, and Craig H. Kuder for there shared expertise in schweinfurthins. Dr. Jacqueline Reilly for technical assistance in handling the animals. Dr. Gary J. Gibson for his input in the study related to extracellular matrix biology of the Swarm rat chondrosarcoma model. Funding through the University of Iowa Sarcoma Multidisciplinary Oncology Group Research Fund and the Holden Comprehensive Cancer Center. We also thank Core facilities including the Central Microscopy Research Facility (Carver College of Medicine) and the Comparative Pathology Laboratory (Department of Pathology, University of Iowa). Gift of the Swarm rat chondrosarcoma LM1 cells from Dr. Christopher Hamm, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago, IL. In accord with university policy, Jeff W. Stevens informs that the author Dr. Jeffrey D. Neighbors is a named inventor on patents held by the University of Iowa Research Foundation that describe preparation of some schweinfurthin analogues, including MeSG, as well as their use as potential anti-cancer agents. Dr. Neighbors is also a founder of the start-up company Terpenoid Therapeutics, Inc. and holds an equity interest in this company. None of the authors received payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. None of the authors (with the exception as noted above for JDN), or his institution, has had a financial relationship, in the 36 months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work.
Funding Information:
Terpenoid Therapeutics Incorporated (Coralville, IA) for donation of the schweinfurthin compound, TTI-3144 (The University of Iowa, Division of Sponsored Programs, Uniform Biological Material Transfer Agreement reference #: N2013090025). Drs. Raymond J. Hohl, David F. Wiemer, and Craig H. Kuder for there shared expertise in schweinfur-thins. Dr. Jacqueline Reilly for technical assistance in handling the animals. Dr. Gary J. Gibson for his input in the study related to extracellular matrix biology of the Swarm rat chondrosarcoma model. Funding through the University of Iowa Sarcoma Multidisciplinary Oncology Group Research Fund and the Holden Comprehensive Cancer Center. We also thank Core facilities including the Central Microscopy Research Facility (Carver College of Medicine) and the Comparative Pathology Laboratory (Department of Pathology, University of Iowa). Gift of the Swarm rat chondrosarcoma LM1 cells from Dr. Christopher Hamm, Ann & Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL. In accord with university policy, Jeff W. Stevens informs that the author Dr. Jeffrey D. Neighbors is a named inventor on patents held by the University of Iowa Research Foundation that describe preparation of some schweinfurthin analogues, including MeSG, as well as their use as potential anti-cancer agents. Dr. Neighbors is also a founder of the start-up company Terpenoid Therapeutics, Inc. and holds an equity interest in this company. None of the authors received payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. None of the authors (with the exception as noted above for JDN), or his institution, has had a financial relationship, in the 36 months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work.
Funding Information:
Conflicts of interest: The complete disclosures of potential conflicts of interest submitted by authors are always provided with the online version of the article. *Dedicated to Margaret and Richard Ling and family for the loss of their son Ben to chondrosarcoma and for their continued dedication in support to sarcoma research and sarcoma patient family members. Grant sponsor: Holden Comprehensive Cancer Center, University of Iowa; Grant sponsor: University of Iowa Sarcoma Multidisciplinary Oncology Group Research Fund. Correspondence to: Jeff W. Stevens (T: þ1-319-594-5153; F: þ1-319-384-9307; E-mail: jeff-stevens@uiowa.edu)
Publisher Copyright:
© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
PY - 2018/4
Y1 - 2018/4
N2 - New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well-differentiated hyaline cartilage-like extracellular matrix (e.g., collagen II and proteoglycan-rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5′-methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate- to high-grade chondrosarcoma model, having a hyaline cartilage-like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC 50 ) of 35 nM MeSG; approximately 300-fold less than freshly isolated rat chondrocytes (IC 50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17-day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult-to-treat intermediate-to high-grade hyaline cartilage-like chondrosarcoma.
AB - New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well-differentiated hyaline cartilage-like extracellular matrix (e.g., collagen II and proteoglycan-rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5′-methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate- to high-grade chondrosarcoma model, having a hyaline cartilage-like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC 50 ) of 35 nM MeSG; approximately 300-fold less than freshly isolated rat chondrocytes (IC 50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17-day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult-to-treat intermediate-to high-grade hyaline cartilage-like chondrosarcoma.
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U2 - 10.1002/jor.23753
DO - 10.1002/jor.23753
M3 - Article
C2 - 28960476
AN - SCOPUS:85034627538
SN - 0736-0266
VL - 36
SP - 1283
EP - 1293
JO - Journal of Orthopaedic Research
JF - Journal of Orthopaedic Research
IS - 4
ER -