Abstract
Doxycycline (DXC) is a tetracycline antibiotic which has been proposed as a breast cancer radiosensitizer by specifically reducing the expression of the DNA repair enzyme DNA PK in breast cancer initiating cells. Since DXC presents favorable pharmacokinetics properties including the capacity to cross the blood-brain barrier, it has been hypothesized that it could radiosensitize brain tumors as well. We have investigated the radiosensitizing capacity of DXC towards human glioma initiating cells (GIC)-driven orthotopic glioblastomas (GB) in NOD/SCID mice that faithfully mimic the growth properties of the clinical tumors of origin. DXC at 10 mg/Kg body weight was subcutaneously delivered daily, 5 days/week for 4 weeks. At the same time, radiotherapeutic fractions of 0.25 Gy to the head were delivered every 3–4 days (twice/week) for 15 weeks. No survival advantage was observed in DXC-treated mice as compared to vehicle-treated mice by this radiosensitizing protocol. On the contrary, skin damage with hair loss and deep ulcers were observed after 4 weeks in DXC-treated mice leading to discontinuation of drug treatment. These results do not support the use of DXC as a radiosensitizer for brain tumors and indicate skin damage as an important side effect of DXC.
Highlights
Glioblastoma (GB-WHO grade IV) is the most common malignant brain tumor in adults; it is almost invariably lethal in 10–12 months
Resistance to ionizing radiation (IR) may be linked to specific tumor cell populations often displaying stem properties [2, 3]
DXC has been further reported to reduce in breast tumor initiating cells the expression of the DNA-PK protein, which is involved in DNA repair of IR-induced damage
Summary
Glioblastoma (GB-WHO grade IV) is the most common malignant brain tumor in adults; it is almost invariably lethal in 10–12 months. Resistance to IR may be linked to specific tumor cell populations often (but not invariably) displaying stem properties (glioma initiating cells – GIC) [2, 3]. DXC may function as an inhibitor of mitochondrial biogenesis by binding to the small subunit of the mitochondrial ribosome which shows a number of conserved properties and protein homologies with ancestor bacterial ribosomes [4]. DXC has been further reported to reduce in breast tumor initiating cells the expression of the DNA-PK protein, which is involved in DNA repair of IR-induced damage. DXC has shown favorable pharmacokinetics properties, with nearly 100% oral absorption, an 18–22 h serum half-life and the capacity to cross the blood-brain barrier, suggesting its use as a radio-sensitizer of brain tumors.
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