Antiandrogen Therapy with Hydroxyflutamide or Androgen Receptor Degradation Enhancer ASC-J9 Enhances BCG Efficacy to Better Suppress Bladder Cancer Progression.
Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5β1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
Zhiqun
Z
Shang
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China.
Yanjun
Y
Li
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. Department of Urology, Tianjin Third Central Hospital, Tianjin, China.
Minghao
M
Zhang
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
Jing
J
Tian
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China.
Ruifa
R
Han
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China.
Chih-Rong
CR
Shyr
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
Edward
E
Messing
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
Shuyuan
S
Yeh
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York. chang@urmc.rochester.edu yuanjie_niu@163.com.
Yuanjie
Y
Niu
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China. George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York. Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan. chang@urmc.rochester.edu yuanjie_niu@163.com.
Chawnshang
C
Chang
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D011944:Receptors, Androgen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D000726:Androgen Antagonists; D001500:BCG Vaccine; D003474:Curcumin; D005485:Flutamide; D039081:Integrin alpha5beta1; D015850:Interleukin-6; D011944:Receptors, Androgen; C471106:ASC-J9 compound; C014290:hydroxyflutamide