Salah Mohamed El Sayed

Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.

Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (Anticancer effects of 3-bromopyruvate through antagonizing Warburg effect)

Cancer cells undergo an increased steady-state ROS condition compared to normal cells. Among the major metabolic differences between cancer cells and normal cells is the dependence of cancer cells on glycolysis as a major source of energy even in the presence of oxygen (Warburg effect). In Warburg effect, glucose is catabolized to lactate that is extruded through monocarboxylate transporters to the microenvironment of cancer cells, while in normal cells, glucose is metabolized into pyruvate that is not extruded. Pyruvate is a potent antioxidant, while lactate has no antioxidant effect. Pyruvate in normal cells may be further metabolized to acetyl CoA and then through Krebs cycle with production of antioxidant intermediates e.g. citrate, malate and oxaloacetate together with the reducing equivalents (NADH.H+). Through activity of mitochondrial transhydrogenase, NADH.H+ replenishes NADPH.H+, coenzyme of glutathione reductase which replenishes reduced form of glutathione (potent antioxidant). This enhances antioxidant capacities of normal cells, while cancer cells exhibiting Warburg effect may be deprived of all that antioxidant capabilities due to loss of extruded lactate (substrate for Krebs cycle). Although intrinsic oxidative stress in cancer cells is high, it may be prevented from reaching progressively increasing levels that are cytotoxic to cancer cells. This may be due to some antioxidant effects exerted by hexokinase II (HK II) and NADPH.H+ produced through HMP shunt. Glycolytic phenotype in cancer cells maintains a high non-toxic oxidative stress in cancer cells and may be responsible for their malignant behavior. Through HK II, glycolysis fuels the energetic arm of malignancy, the mitotic arm of malignancy (DNA synthesis through HMP shunt pathway) and the metastatic arm of malignancy (hyaluronan synthesis through uronic acid pathway) in addition to the role of phosphohexose isomerase (autocrine motility factor). All those critical three arms start with the substrate G6P that is a direct product of HK II. 3-bromopyruvate (3BP, inhibitor of HK II) may prove as a promising anticancer and antimetastatic agent based on antagonizing the Warburg effect and disturbing the malignant behavior in cancer cells.

Anatomical Sites for Practicing Wet Cupping Therapy (Al-Hijamah): In Light of Modern Medicine and Prophetic Medicine

Wet cupping therapy (WCT) is increasingly practiced worldwide, especially in hospitals of China and Germany. Al-hijamah is WCT of prophetic medicine. Al-hijamah was recently reported to do better than Chinese WCT. Alhijamah filters and clears blood and interstitial fluids from causative pathological substances (CPS) including disease-causing substances (DCS) and disease-related substances (DRS) according to the evidence-based Taibah theory. This occurs via a percutaneous pressure-dependent and size-dependent filtration of capillary blood of skin circulation. This explains why Al-hijamah treats diseases with different pathogeneses e.g. headache and rheumatoid arthritis. Hijamatology is a novel term describing the science of education, qualification, practice and research related to Al-hijamah. Al-hijamah was described by Prophet Mohammad (Muhammad) peace be upon him as one of the best remedies: “The best among what you use in therapy is Al-hijamah”. No published report is there to guide researchers, physicians and practitioners to the best anatomical sites for practicing Al-hijamah for treating different diseases as this science is still in its beginning and may benefit from future research. Based on our background in prophetic medicine, anatomy, medicine and our practice, we review here prophetic medicine remedies, indications and anatomical sites that may be suitable for practicing Al-hijamah. Suitable anatomical sites for practicing Alhijamah differ from disease to disease. In prophetic medicine, Al-hijamah was practiced at skin overlying and near sites of pathology e.g. skin overlying skull vertex, dorsal surface of the foot, thigh region and at general sites e.g. kahel region (mainly skin overlying 7th cervical vertebra) and akhdayin (both sides of the neck posterior to ears). We report here a novel technique (Salah’s technique) for practicing Al-hijamah safely at some special anatomical sites. In conclusion, Al-hijamah is better to be practiced at sites of pathology (for local clearance), at back region and back of neck (for general blood clearance).

Al-hijamah and oral honey for treating thalassemia, conditions of iron overload, and hyperferremia: toward improving the therapeutic outcomes.

Iron overload causes iron deposition and accumulation in the liver, heart, skin, and other tissues resulting in serious tissue damages. Significant blood clearance from iron and ferritin using wet cupping therapy (WCT) has been reported. WCT is an excretory form of treatment that needs more research efforts. WCT is an available, safe, simple, economic, and time-saving outpatient modality of treatment that has no serious side effects. There are no serious limitations or precautions to discontinue WCT. Interestingly, WCT has solid scientific and medical bases (Taibah mechanism) that explain its effectiveness in treating many disease conditions differing in etiology and pathogenesis. WCT utilizes an excretory physiological principle (pressure-dependent excretion) that resembles excretion through renal glomerular filtration and abscess evacuation. WCT exhibits a percutaneous excretory function that clears blood (through fenestrated skin capillaries) and interstitial fluids from pathological substances without adding a metabolic or detoxification burden on the liver and the kidneys. Interestingly, WCT was reported to decrease serum ferritin (circulating iron stores) significantly by about 22.25% in healthy subjects (in one session) and to decrease serum iron significantly to the level of causing iron deficiency (in multiple sessions). WCT was reported to clear blood significantly of triglycerides, low-density lipoprotein (LDL) cholesterol, total cholesterol, uric acid, inflammatory mediators, and immunoglobulin antibodies (rheumatoid factor). Moreover, WCT was reported to enhance the natural immunity, potentiate pharmacological treatments, and to treat many different disease conditions. There are two distinct methods of WCT: traditional WCT and Al-hijamah (WCT of prophetic medicine). Both start and end with skin sterilization. In traditional WCT, there are two steps, skin scarification followed by suction using plastic cups (double S technique); Al-hijamah is a three-step procedure that includes skin suction using cups, scarification (shartat mihjam in Arabic), and second skin suction (triple S technique). Al-hijamah is a more comprehensive technique and does better than traditional WCT, as Al-hijamah includes two pressure-dependent filtration steps versus one step in traditional WCT. Whenever blood plasma is to be cleared of an excess pathological substance, Al-hijamah is indicated. We will discuss here some reported hematological and therapeutic benefits of Al-hijamah, its medical bases, methodologies, precautions, side effects, contraindications, quantitative evaluation, malpractice, combination with oral honey treatment, and to what extent it may be helpful when treating thalassemia and other conditions of iron overload and hyperferremia.

The Antioxidant Glycolysis Inhibitor (Citric Acid) Induces a Dose-dependent Caspase-mediated Apoptosis and Necrosis in Glioma Cells

Background: Glioma tumors are still a big challenge being incurable with current chemotherapy and radiotherapy treatments. Surgical treatment of glioma needs adjuvant effective targeting therapy for better glioma cell treatment. Citrate is a well-known antioxidant organic acid abundant in citrus fruits and is an inhibitor of glycolysis through targeting the glycolytic enzyme phosphofructokinase, one of the key enzymes of glycolysis. Citrate is a natural product that is formed inside mitochondria during Krebs cycle to the extent that Krebs cycle is often referred to as citric acid cycle. It was reported that glioma cells are driven by glycolysis where glioma cells upregulates the expression of glycolysis genes and enzymes. Objectives: This aim is to investigate effect of citrate on glioma cells viability, morphology and moge of glioma-induced cell death. Methodology: In this study, citrate-induced glioma cell death was investigated using MTT assay, western blot analysis and flowcytometric evaluation was done to C6 glioma cells. Results: Citrate induced a potent anti-glioma effect by significantly decreasing viability of C6 glioma cells in a dose-dependent manner. Flow cytometric analysis revealed that at 5 mM, citrate induced a caspase-dependent apoptotic glioma cell death. Higher doses of citrate (9 mM) induced necro-apoptotic glioma cell death. Conclusion: citrate may be a promising therapeutic treatment for glioma and glioblastoma. Citrate-rich fruits are strongly recommended as a nutritional treatment for glioma patients.