Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells

Abstract

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.

Assessing the photodynamic therapeutic effects of 5‑aminolevulinic acid on human colon cancer cells using light‑emitting diodes

“…Previous studies have demonstrated that the effects of 5-ALA can be reversed with Z-VAD(OMe)-FMK, indicating apoptosis in some conditions (29). Others have demonstrated that 5-ALA causes cell death through autophagy (30,31), whereas some researchers claim that neither pathway is involved (32). The present study observed that the death of SW480 cells was partially reversed by 3-methyladenine, whereas Z-VAD(OMe)-FMK did not exert an effect.…”

Emerging Trends in Nanomaterials for Antibacterial Applications

“…Nanomaterials for PDT applications include metals, upconversion nanoparticles, carbon-based nanomaterials, two-dimensional (2D) nanomaterials, quantum dots (QDs), etc. [36][37][38][39][40][41] PDT can be used to treat infectious diseases without the specter of drug resistance like with antibiotic treatment. 42,43 In this way, PDT can be applied to all types of microorganisms including bacteria.…”

CD4+ memory T cells infected with latent HIV-1 are susceptible to drugs targeting telomeres

“…For example, widely used antibiotic doxycycline was discovered to have inhibitory effect on DNA-PKs involved in DSBs repair, and to have anticancer activity. It is considered as supporting compound in anticancer treatments [66][67][68][69][70][71][72].…”