Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis.

Dichloroacetate (DCA) is a promising safe anticancer drug that cured a patient with chemoresistant non-Hodgkin's lymphoma and treated lactic acidosis effectively. The well-known mechanism of DCA action is through stimulating Krebs cycle (stimulating pyruvate dehydrogenase via inhibiting pyruvate dehydrogenase kinase). This prevents lactate formation (Warburg effect) depriving cancer cells of lactate-based benefits e.g. angiogenesis, chemoresistance and radioresistance. Here, we introduce novel evidence-based hypotheses to explain DCA-induced anticancer effects. On pharmacological and biochemical bases, we hypothesize that DCA is a structural antagonist of acetate competing with it for target enzymes and biological reactions. We hypothesize that DCA exerts its anticancer effects via depriving cancer of acetate benefits. We hypothesize also that acetate is an antidote of DCA capable of treating DCA toxicity. Many reports support our hypotheses. Acetate is vital for cancer cells (tumors depend on acetate) and DCA is structurally similar to acetate. DCA exerts opposite effects to acetate. Acetate caused a decrease in serum potassium, phosphorus and glucose, and an increase in serum lactate, citrate, free fatty acids and ketone bodies (serum acetoacetate and beta-hydroxybutyrate levels). Acetate decreased the proportion of active (dephosphorylated) pyruvate dehydrogenase in perfused rat heart. DCA produced quite opposite effects. Intravenous infusion of acetate produced metabolic alkalemia while DCA caused minimal effects on acid-base status. Acetate is important for cancer cells metabolism and survival as elevated acetate can drive resistance to targeted cancer treatments. Acetate is required for epidermal growth factor receptor vIII mutation in lethal brain tumors. Experimentally, DCA inhibited acetate oxidation in hearts of normal rats and reversed inhibitory effects of acetate on the oxidation of glucose. During presence of DCA with no glucose in heart perfusions with [1-14C]acetate, DCA decreased the specific radioactivity of acetyl CoA and its product citrate. This proves our hypotheses that DCA is an antimetabolite that antagonizes acetate for vital reactions in cancer cells. Acetate may be used as an antidote to combat DCA toxicity.

Al-hijamah (wet cupping therapy of prophetic medicine) significantly and safely reduces iron overload and oxidative stress in thalassemic children: a novel pilot study.

BACKGROUND: Thalassemia 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 STUDY: Our study aimed at investigating the safety, iron chelation, pharmacological potentiation and oxidant clearance effects exerted by Al-hijamah to thalassemic children. PATIENTS AND METHODS: Ethical 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. RESULTS: Al-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. CONCLUSION: Al-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.

The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view.

3-Bromopyruvate (3BP) is a promising effective anticancer drug against many different tumors in children and adults. 3BP exhibited strong anticancer effects in both preclinical and human studies e.g. energy depletion, oxidative stress, anti-angiogenesis, anti-metastatic effects, targeting cancer stem cells and antagonizing the Warburg effect. There is no report about 3BP metabolism to guide researchers and oncologists to improve clinical practice and prevent drug resistance. In this article, we provide evidences that 3BP is metabolized through glutathione (GSH) conjugation as a novel report where 3BP was confirmed to be attached to GSH followed by permanent loss of pharmacological effects in a picture similar to cisplatin. Both cisplatin and 3BP are alkylating agents. Reported decrease in endogenous cellular GSH content upon 3BP treatment was confirmed to be due to the formation of 3BP-GSH complex i.e. GSH consumption for conjugation with 3BP. Cancer cells having high endogenous GSH exhibit resistance to 3BP while 3BP sensitive cells acquire resistance upon adding exogenous GSH. Being a thiol blocker, 3BP may attack thiol groups in tissues and serum proteins e.g. albumin and GSH. That may decrease 3BP-induced anticancer effects and the functions of those proteins. We proved here that 3BP metabolism is different from metabolism of hydroxypyruvate that results from metabolism of D-serine using D-amino acid oxidase. Clinically, 3BP administration should be monitored during albumin infusion and protein therapy where GSH should be added to emergency medications. GSH exerts many physiological effects and is safe for human administration both orally and intravenously. Based on that, reported GSH-induced inhibition of 3BP effects makes 3BP effects reversible, easily monitored and easily controlled. This confers a superiority of 3BP over many anticancer agents.