Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy.
There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans.
Authors' Affiliations: Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh; and Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.
Avani R
AR
Vyas
Eun-Ryeong
ER
Hahm
Julie A
JA
Arlotti
Simon
S
Watkins
Donna Beer
DB
Stolz
Dhimant
D
Desai
Shantu
S
Amin
Shivendra V
SV
Singh
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001798:Blood Proteins / Q000032:analysis; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017879:Isothiocyanates / Q000494:pharmacology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013454:Sulfoxides
D016588:Anticarcinogenic Agents; D000962:Antimalarials; D001798:Blood Proteins; D017879:Isothiocyanates; D013454:Sulfoxides; D002738:Chloroquine; C016766:sulforaphane