Radiosensitization of orthotopic GIC-driven glioblastoma by doxycycline causes skin damage
- PDF / 2,809,234 Bytes
- 6 Pages / 595.276 x 790.866 pts Page_size
- 110 Downloads / 144 Views
SHORT REPORT
Open Access
Radiosensitization of orthotopic GIC-driven glioblastoma by doxycycline causes skin damage Guido Frosina1* , Daniela Marubbi2,3, Diana Marcello1 and Antonio Daga2
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 DXCtreated 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. Keywords: glioma animal models, radiosensitization, doxycycline
Background Glioblastoma (GB-WHO grade IV) is the most common malignant brain tumor in adults; it is almost invariably lethal in 10–12 months. GB appears as infiltrating lesions on MRI or CT often characterized by central necrosis, perilesional edema and abnormal vasculature [1]. Radiotherapy for primary GB involves a total ionizing radiation (IR) dose to the tumor of 54–60 Gy given in 1.8–2 Gy fractions 5 days/week. The tumor usually relapses in a few months after which re-irradiation is in most cases ineffective. Resistance to IR may be linked to specific tumor cell populations often (but not invariably) displaying stem properties (glioma initiating cells – GIC) [2, 3]. Since its FDA-approval in 1967, doxycycline (DXC) has been used as a broad-spectrum antibiotic targeting bacterial ribosomes. In mammalian cells, 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]. Clinical trials with DXC serendipitously showed positive therapeutic effects in lymphoma patients [5, 6], generating the hypothesis that DXC treatment may specifically reduce the oxidative mitochondrial capacity and the glycolytic activity of cancer cells [7]. 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. Consistently, the cells were radio-sensitized up
Data Loading...
