Modulating mitochondrial morphology enhances antitumor effect of 5-ALA-mediated photodynamic therapy both in vitro and in vivo.

Abstract

5-aminolevulinic acid mediated PDT (5-ALA-PDT) is an approved therapeutic procedure for treating carcinomas of the cervix. However, when employed as a monotherapy, 5-ALA-PDT could not produce satisfactory results toward large and deep tumors. Therefore, developing a method to improve the efficacy of 5-ALA-PDT becomes important. In this study, we demonstrate an enhanced antitumor effect of 5-ALA-PDT by the modulation of mitochondrial morphology. The mitochondria in the cells were regulated into tubular mitochondria or fragmented mitochondria through over expression of Drp1 or Mfn2. Then these cells were treated with identical dose of 5-ALA-PDT. Our results suggest that HeLa cells predominantly containing fragmented mitochondria were more sensitive to 5-ALA-PDT than the cells predominantly containing tubular mitochondria. The morphology of mitochondria changed as the cell cycle progressed, with tubular mitochondria predominantly exhibited in the S phase and uniformly fragmented mitochondria predominantly displayed in the M phase. Paclitaxel significantly increased the population of M-phase cells, while 5-fluorouracil significantly increased the population of S-phase cells in xenograft tumors. Furthermore, low-dose paclitaxel significantly increased the antitumor effects of PDT. However, 5-fluorouracil didn't improve the antitumor effects of PDT. These results demonstrated an enhanced antitumor effect of 5-ALA-PDT from the modulation of mitochondrial morphology. We anticipate that our results will provide an insight for selecting potential chemotherapeutic agents to combine with PDT for tumor treatment.

• Authors: Hongyou Zhao, Rong Yin, Ying Wang, Yuan-Hao Lee, Ting Luo, Jiaying Zhang, Haixia Qiu, Stephen Ambrose, Lijie Wang, Jie Ren, Jie Yao, Defu Chen, Yucheng Wang, Zhipin Liang, Jie Zhen, Sumin Wu, Zulin Ye, Jing Zeng, Naiyan Huang, Ying Gu
• Journal: Journal of photochemistry and photobiology. B, Biology (J Photochem Photobiol B) Vol. 176 Pg. 81-91 (Nov 2017) ISSN: 1873-2682 [Electronic] Switzerland
• PMID: 28964889 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• Photosensitizing Agents
• Reactive Oxygen Species
• Aminolevulinic Acid
• GTP Phosphohydrolases
• MFN2 protein, human
• DNM1L protein, human
• Dynamins
• Paclitaxel
• Fluorouracil

Topics

• Aminolevulinic Acid (chemistry, therapeutic use, toxicity)
• Animals
• Antineoplastic Agents (chemistry, therapeutic use, toxicity)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects, radiation effects)
• Dynamins
• Fluorouracil (therapeutic use, toxicity)
• GTP Phosphohydrolases (genetics, metabolism)
• HeLa Cells
• Humans
• Immunohistochemistry
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Fluorescence
• Microtubule-Associated Proteins (genetics, metabolism)
• Mitochondria (chemistry, drug effects, metabolism, radiation effects)
• Mitochondrial Proteins (genetics, metabolism)
• Neoplasms (drug therapy, mortality, pathology)
• Paclitaxel (therapeutic use, toxicity)
• Photochemotherapy
• Photosensitizing Agents (chemistry, therapeutic use, toxicity)
• Plasmids (genetics, metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Survival Rate
• Transplantation, Heterologous