A novel photodynamic therapy targeting cancer cells and tumor-associated macrophages.

Abstract

Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with M-chlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G-chlorin). The subcellular localization of M-chlorin was observed by confocal microscopy, and the M-chlorin PDT effects against TAMs including THP-1-induced M2-polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT.

• Authors: Noriyuki Hayashi, Hiromi Kataoka, Shigenobu Yano, Mamoru Tanaka, Kazuhiro Moriwaki, Haruo Akashi, Shugo Suzuki, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Takashi Joh
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 2 Pg. 452-60 (Feb 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25512617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Porphyrins
• chlorin
• Caspase 3
• Caspase 7

Topics

• Allografts
• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, enzymology, pathology)
• Endoplasmic Reticulum (drug effects, metabolism)
• Female
• Humans
• Immunohistochemistry
• Inhibitory Concentration 50
• Lysosomes (drug effects, metabolism)
• Macrophages (drug effects, metabolism, pathology)
• Mice, Inbred BALB C
• Photochemotherapy
• Porphyrins (chemistry, pharmacology, therapeutic use)
• Stomach Neoplasms (drug therapy, enzymology, pathology)
• Subcellular Fractions (drug effects, metabolism)