Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2), KG-1 (ABCB1) and HepG2 cells (ABCB1 and ABCG2). Interestingly, although side population (SP) cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

BackgroundThalassemia is a major health problem due to iron overload, iron deposition and oxidative stress-induced tissue damage. Here, we introduce Al-hijamah (a minor surgical excretory procedure) as a novel percutaneous iron excretion therapy. Al-hijamah is a wet cupping therapy of prophetic medicine, and prophet Muhammad, peace be upon him, strongly recommended Al-hijamah, saying: “The best of your treatment is Al-hijamah”.Aim of the studyOur study aimed at investigating the safety, iron chelation, pharmacological potentiation and oxidant clearance effects exerted by Al-hijamah to thalassemic children.Patients and methodsEthical committee’s approval and patients’ written agreement consents were obtained. We treated 20 thalassemic children (15 males and five females aged 9.07±4.26 years) with iron chelation therapy (ICT) plus Al-hijamah (using sterile disposable sets and in a complete aseptic environment) vs a control group treated with ICT only. This clinical trial was registered in the ClinicalTrial.gov registry under the name “Study of the Therapeutic Benefits of Al-hijamah in Children with Beta Thalassemia Major” (identifier no NCT 02761395) on 30 January 2016.ResultsAl-hijamah was quite simple, safe, effective, tolerable (with no side effects) and time-saving procedure (30–60 minutes). A single session of Al-hijamah significantly reduced iron overload (P<0.001) in all thalassemic children. Al-hijamah significantly decreased serum ferritin by 25.22% (from 3,778.350±551.633 ng/mL to 2,825.300±558.94 ng/mL), significantly decreased oxidative stress by 68.69% (P<0.05; serum malondialdehyde dropped from 42.155±12.42 to 13.195±0.68 nmol/L), exerted pharmacological potentiation to ICT and significantly increased total antioxidant capacity (P<0.001) by 260.95% (from 13.195±0.68 nmol/L to 42.86±12.40 nmol/L through excreting reactive oxygen species). Moreover, therapeutic indices for evaluating Al-hijamah were promising.ConclusionAl-hijamah is a novel, safe, effective percutaneous iron excretion therapy through percutaneous iron excretion with minimal blood loss in agreement with the evidence-based Taibah mechanism. Al-hijamah is an effective outpatient hematological procedure that is safer than many pediatric procedures such as catheterization, hemofiltration and dialysis. Increasing the number of cups during Al-hijamah session or the number of sessions reduces iron overload more strongly. Medical practice of Al-hijamah is strongly recommended in hospitals.

No abstract

Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

No abstract