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Background <p>Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, characterized by infiltrative growth, resistance to chemotherapy and radiotherapy, and an immune-suppressive microenvironment. Interstitial Photodynamic Therapy (iPDT), which involves oral ALA administration and localized light activation, offers a promising approach by killing tumor cells, disrupting tumor vasculature, and stimulating the immune response. However, iPDT faces limitations due to the blood–brain barrier (BBB), insufficient irradiation of satellite and margin tumors, hypoxia within the tumor microenvironment, and glioma cell repair mechanisms. These factors collectively contribute to the suboptimal efficacy of iPDT, emphasizing the need for combined therapeutic strategies to improve outcomes. Some in-vitro research on D, L-methadone, which enhances chemotherapy and ALA-PDT, has caught our interest, although it remains controversial.</p> Methods <p>The levels of the μ-opioid receptor (MOR) were measured in multiple GBM cell lines. Multiple GBM cell lines (A172, U251, GB14) were treated with 2.5&#xa0;µg/ml and 10&#xa0;µg/ml D, L-methadone in combination with sublethal-dose ALA-PDT to mimic the limitations of PDT. A MOR antagonist, naloxone (NAL), was used to inhibit the potential role of methadone. Cell viability, apoptosis, PpIX, and ROS were examined.</p> Results <p>The expression level of MOR in GBM cell lines was low. In the A172 cell line, 10&#xa0;µg/ml methadone enhanced sublethal-dose ALA-PDT-induced apoptosis; however, in the U251 and GB14 cell lines, neither 2.5&#xa0;µg/ml methadone nor 10&#xa0;µg/ml methadone could enhance ALA-PDT-induced apoptosis. The viability of the three cell lines was unaffected by methadone combined with ALA-PDT. No reversal effect of naloxone on methadone was observed. Data show that methadone did not significantly enhance PpIX accumulation or ROS generation when combined with ALA-PDT.</p> Conclusions <p>A general sensitizing effect of methadone on ALA-PDT was not observed in this in vitro experiment involving multiple GBM cell lines. The sensitizing effect of methadone on ALA-PDT may depend on the specific cell line used. Therefore, the recommendation to use methadone as a sensitizer for ALA-PDT in the treatment of GBM should be made with caution.</p>

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Investigation of the impact of D, L-methadone on ALA-PDT in multiple glioblastoma cell lines

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Linglin Zhang,
  • Heike Pohla,
  • Adrian Rühm,
  • Herbert Stepp,
  • Ronald Sroka

摘要

Background

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, characterized by infiltrative growth, resistance to chemotherapy and radiotherapy, and an immune-suppressive microenvironment. Interstitial Photodynamic Therapy (iPDT), which involves oral ALA administration and localized light activation, offers a promising approach by killing tumor cells, disrupting tumor vasculature, and stimulating the immune response. However, iPDT faces limitations due to the blood–brain barrier (BBB), insufficient irradiation of satellite and margin tumors, hypoxia within the tumor microenvironment, and glioma cell repair mechanisms. These factors collectively contribute to the suboptimal efficacy of iPDT, emphasizing the need for combined therapeutic strategies to improve outcomes. Some in-vitro research on D, L-methadone, which enhances chemotherapy and ALA-PDT, has caught our interest, although it remains controversial.

Methods

The levels of the μ-opioid receptor (MOR) were measured in multiple GBM cell lines. Multiple GBM cell lines (A172, U251, GB14) were treated with 2.5 µg/ml and 10 µg/ml D, L-methadone in combination with sublethal-dose ALA-PDT to mimic the limitations of PDT. A MOR antagonist, naloxone (NAL), was used to inhibit the potential role of methadone. Cell viability, apoptosis, PpIX, and ROS were examined.

Results

The expression level of MOR in GBM cell lines was low. In the A172 cell line, 10 µg/ml methadone enhanced sublethal-dose ALA-PDT-induced apoptosis; however, in the U251 and GB14 cell lines, neither 2.5 µg/ml methadone nor 10 µg/ml methadone could enhance ALA-PDT-induced apoptosis. The viability of the three cell lines was unaffected by methadone combined with ALA-PDT. No reversal effect of naloxone on methadone was observed. Data show that methadone did not significantly enhance PpIX accumulation or ROS generation when combined with ALA-PDT.

Conclusions

A general sensitizing effect of methadone on ALA-PDT was not observed in this in vitro experiment involving multiple GBM cell lines. The sensitizing effect of methadone on ALA-PDT may depend on the specific cell line used. Therefore, the recommendation to use methadone as a sensitizer for ALA-PDT in the treatment of GBM should be made with caution.