title: Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer.
abstract: The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Huang-Chiao
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Srivalleesha
authors.initials: S
authors.lastname: Mallidi
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chiang
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Mai
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Ruth
authors.initials: R
authors.lastname: Goldschmidt
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Neema
authors.initials: N
authors.lastname: Ebrahim-Zadeh
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts.
authors.forename: Imran
authors.initials: I
authors.lastname: Rizvi
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, MGH, Boston, Massachusetts. Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts. thasan@mgh.harvard.edu.
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004355:Drug Stability; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000032:analysis / Q000235:genetics; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics; D053758:Nanoparticles; D009363:Neoplasm Proteins / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010778:Photochemotherapy; D011166:Porphyrins / Q000737:chemistry; D000077022:Survivin; D016896:Treatment Outcome
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D011166:Porphyrins; C406962:SLC16A4 protein, human; D000077022:Survivin; C504224:benzoporphyrin D; D000077146:Irinotecan; D002166:Camptothecin