Targeted photodynamic therapy for prostate cancer: inducing apoptosis via activation of the caspase-8/-3 cascade pathway.
The limitation of specific delivery of photosensitizers to tumor sites, represents a significant shortcoming of photodynamic therapy (PDT) application at present. Prostate-specific membrane antigen (PSMA), a validated biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. The present study focuses on the investigation of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2.1) for a targeted PDT application and the mechanism of its mediated-cell death in prostate cancer cells. Multiple fluorescence labeling methods were employed to monitor PDT-treated prostate cancer cells by confocal laser scanning microscopy. Our results demonstrate that Ppa-conjugate 2.1 mediated apoptosis is specific to PSMA+ (positive) LNCaP cells, but not PSMA- (negative) PC-3 cells. Furthermore, these results indicate that following PDT, the activation of caspase-8, -3, -9, cleavage of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation is sequential. The appearance of cleaved beta-actin further supported involvement of caspase-3. Specific caspase inhibitor blocking studies reveal that the caspase-8/-3 cascade pathway plays a key role in apoptosis of LNCaP cells induced by Ppa-conjugate 2.1. The demonstrated selective targeting and efficacy of this agent suggests that targeted PDT could serve as an alternative treatment option for prostate cancer.
Liu
Tiancheng
T
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
Wu
Lisa Y
LY
Choi
Joseph K
JK
Berkman
Clifford E
CE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D008297:Male; D018613:Microscopy, Confocal; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D017319:Photosensitizing Agents; D002734:Chlorophyll; C040298:pyropheophorbide a; D011065:Poly(ADP-ribose) Polymerases; D017430:Prostate-Specific Antigen; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8