Targeting the Warburg Effect with Glucosodiene: A Case Report of a 43-year-old Female after Mastectomy of the right breast and axillary clearance with Successful First Case Treatment for Metastatic Triple Negative Breast Cancer (TNBC) of Bone.

Received: 27-Aug-2023, Manuscript No. OAR-23-111377; Accepted: 02-Oct-2023, Pre QC No. OAR-23-111377 (PQ); Editor assigned: 30-Aug-2023, Pre QC No. OAR-23-111377 (PQ); Reviewed: 20-Sep-2023, QC No. OAR-23-111377 (Q); Revised: 29-Sep-2023, Manuscript No. OAR-23-111377 (R); Published: 08-Oct-2023

Introduction

Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer that lacks estrogen receptors, progesterone receptors, and Human Epidermal Growth Factor Receptor 2 (HER2). TNBC is considered aggressive and has a higher likelihood of recurrence than other types of breast cancer. One of the reasons for the aggressiveness of TNBC is its reliance on glucose as its primary source of energy, which is known as the Warburg effect. This reliance on glucose makes TNBC cells more vulnerable to certain treatments that target glucose metabolism, such as some chemotherapy drugs. In this context, the development of glucosodiene molecules that induce tumour hyperthermia and dissolve cancer cells from within by breaking down glucose molecules into carbon dioxide and water, generating energy that alkali elements utilize to dissolve cancer cells, has been proposed. This approach challenges the traditional notion of eliminating cancer cells and proposes using a localized concentration of alkali elements to dissolve cancer cells from within. Animal experiments and histological observations have shown the validity of this theory, and ongoing research is focused on developing new targeted therapies for TNBC [1, 2].

Glucosodiene is an isomer of glucose that is characterized by alkaline properties. It is prepared by a substitution reaction, which is carried out by dissolving sodium bicarbonate with dextrose and heating it under certain reaction conditions to produce the alkaline glucose isomer, Glucosodiene. This form of glucose is likely to inhibit glucose metabolism within the tumour, known as the Warburg effect, and may potentially limit glucose activity within the tumour, which could activate p53. In this study, we investigate the effect of glucosodiene on a woman with advanced-stage breast cancer who consumed it as a dietary supplement on the development and treatment of her condition, as well as evaluate the toxicity and therapeutic activity through clinical indicators [3].

Case Presentation

Patient information

The patient is a 43-year-old female of white race and Arab ethnicity diagnosed with metastatic right breast cancer (invasive mammary carcinoma) that has spread to her lymph nodes and bones. She presented with a 3 cm palpable mass, pain, fatigue, and weight loss in the upper outer quadrant of her right breast, which was also detected through mammography to have speculated and irregular borders. Her lymph nodes in the right axillary region were firm and rubbery, no previous medical history but have a positive family history of hormonal breast cancer.

Treatment plans include chemotherapy, radiation therapy, and hormonal therapy.

Clinical findings timeline

The patient, a 43-year-old premenopausal woman with a positive family history of breast cancer (her mother), was diagnosed with Triple-Negative Breast Cancer (TNBC) in the right breast on August 30, 2022. A mammogram and ultrasound were performed on the same day, revealing a right upper quadrant asymmetry and a retro areolar thickening mass classified as Breast Imaging Reporting and Data System (BIRADS)-5. The ultrasound showed infiltration of the surrounding parenchyma and metastatic lymph nodes in Figure 1.

Figure 1: A mammogram and ultrasound were performed on the same day, revealing a right upper quadrant asymmetry and a retro areolar thickening mass classified as BIRADS, the ultrasound showed infiltration of the surrounding parenchyma and metastatic lymph nodes

Core biopsy confirmed invasive ductal carcinoma GII with positive vascular invasion; negative Estrogen Receptor (ER), negative Progesterone Receptor (PR), and Her2/neu score 1+ negative on September 5, 2022 (Figure 2).

Figure 2: Core biopsy confirmed invasive ductal carcinoma GII with positive vascular invasion; negative Estrogen Receptor (ER), negative Progesterone Receptor (PR), and Her2/neu score 1+ negative

A metastatic workup was conducted on September 6, 2022, including a PET/CT scan, which showed an illdefined infiltrative lesion in the right breast, axillary lymph node metastasis, and no clinical evidence of metastasis in the brain, neck, chest, abdomen, or pelvis.

On March 12, 2023, combined digital tom synthesis, mammography, and breast sonography revealed a speculated mass in the right breast with suspicious segmental calcifications. The patient underwent four cycles of Adriamycin and cyclophosphamide followed by 12 chemotherapy short courses with paclitaxel and carboplatin. However, on April 1, 2023, the tumour size returned to its original size, and aggressive recurrence occurred, causing concerns for the patient.

On April 30, 2023, the patient underwent a modified radical mastectomy with axillary clearance. Histopathological examination of the resected specimens revealed invasive ductal carcinoma, grade 3, with negative ER, negative PR, and Her2/neu negative (score 0).

On June 25, 2023, the patient experienced right leg pain, leading to a bone scan that revealed osseous metastasis in multiple areas, including the right iliac bone, head and trochanteric area of the right femur; right ischium left acetabulum, and trochanteric area of the left femur (Figure 3).

Figure 3: . The patient experienced right leg pain, leading to a bone scan that revealed osseous metastasis in multiple areas, including the right iliac bone, head and trochanteric area of the right femur, right ischium, left acetabulum, and trochanteric area of the left femur

Facing the reality of bone metastasis and fearing the future, the patient sought information and support through websites, social media, and support groups. During her research, she came across information about glucosodiene as a potential treatment targeting metabolic pathways.

Therapeutic interventions

Starting from July 15, 2023, the patient began taking glucosodiene as an oral supplement (100 ml) once daily at 9 pm for 15 days. Additionally, the patient adopted a lowcarbohydrate diet, focusing on vegetables, proteins, and fats. After the fifth day of treatment, the patient experienced improvement and was able to walk, alleviating the severe pain in both legs following the mastectomy.

On July 27, 2023, an isotopic bone scan with dual-phase bone scintigraphy showed stable tracer uptake in the previously identified areas, with mild hyperemic changes during the blood pool phase. The rest of the skeleton displayed homogeneous tracer distribution without active or cold focal lesions. Follow-up bone scans were recommended (Figure 4).

Figure 4: An isotopic bone scan with dual-phase bone scintigraphy showed stable tracer uptake in the previously identified areas, with mild hyperemic changes during the blood pool phase. The rest of the skeleton displayed homogeneous tracer distribution without active or cold focal lesions

A Dual X-Ray Absorptiometry (DEXA) scan was performed on July 30, 2023, to assess the patient's bone density. The results indicated low bone density and an osteoporosis diagnosis, with the left femur showing the lowest Bone Mineral Density (BMD) measurement. The patient's fracture risk was deemed high, and treatment initiation or adjustment was recommended. Follow-up examinations after completing the treatment were advised to monitor the effectiveness of the treatment and the patient's bone health status, based on the World Health Organization (WHO) guidelines (Figure 5).

Figure 5: A DEXA scan was assessing the patient's bone density. The results indicated low bone density and an osteoporosis diagnosis, with the left femur showing the lowest Bone Mineral Density (BMD) measurement. The patient's fracture risk was deemed high, and treatment initiation or adjustment was recommended. Follow-up examinations after completing the treatment were advised to monitor the effectiveness of the treatment and the patient's bone health status, based on the World Health Organization (WHO) guidelines

On August 9, 2023, Magnetic Resonance Imaging (MRI) was revealed no suspicious osseous lesions in the pelvic bone. While there were notable findings related to bilateral old Developmental Dysplasia of the Hips (DDH) as from history taking this patient suffer from congenital hip dislocation from birth. The left hip showed complete dislocation, while the right hip displayed marked lateral subluxation. Additionally, the right hip exhibited secondary degenerative osteoarthrosis, characterized by a flattened femoral head, subarticular sclerosis, cysts, and marrow edema. Degenerative changes were also observed at the left femoral head, along with pseudoarthrosis with the iliac bone. Furthermore, there were bilateral mild hip effusion and left iliopsoas bursitis. In summary, the report of MRI indicated no suspicious osseous lesions in the pelvic bone but confirmed bilateral chronic DDH with secondary degenerative changes (Figure 6).

Figure 6: MRI was revealed no suspicious osseous lesions in the pelvic bone. However, there were notable findings related to bilateral old Developmental Dysplasia of the Hips (DDH) (the Report of MRI printed at 13 august 2023)

Vital indicators prior to treatment

Based on the results, the patient underwent medical tests (liver, kidney, heart, pancreas, blood, blood pH, and urine) before the treatment with glucosodiene on July 15, 2023. The liver function tests showed ASGOT (Aspartate Aminotransferase) levels of 26 U/L (Reference Range: Up to 40 U/L) and ASGPT (Alanine Aminotransferase) levels of 22 U/L (Reference Range: Up to 45 U/L).

The kidney function tests revealed a serum creatinine level of 0.75 mg/dL (Normal: 0.6 mg/dL-1.4 mg/dL) and a blood urea level of 34 mg/dL (Normal: 15-45 mg/dL). The cardiac marker, ALDH (Lactate Dehydrogenase), was measured at 393 U/L (Normal: 230 U/L-460 U/L). In the hematology report, the patient had a hemoglobin level of 12.8 g/dL (Reference Range: 11.7 g/dL-15.5 g/dL), a red blood cell count of 4.45 x 10³ Cells/μL (Reference Range: 3.8 Cells/μL-5.1 x 10³ Cells/μL), and a hematocrit level of 42.6% (Reference Range: 35-45%). The platelet count was 181 x 10³/mm³ (Reference Range: 150 x 10³/mm³-440 x 10³/mm³), and the white blood cell count was 8.93 x 10³/mm³ (Reference Range: 4.5 x 10³/mm³-11.0 x 10³/mm³). The urine examination showed normal physical properties, including random volume, amberyellow colour, aromatic odour, and deposit aspect. The chemical examination revealed an acidic pH of 5.5, negligible trace protein, absence of sugar, acetone, nitrite, and bilirubin, and normal urobilinogen levels. Leukocytes and blood were absent. The microscopic examination showed 4 pus cells/HPF -6 pus cells/HPF (High Power Field), 2 RBCs/HPF-4 RBCs/HPF, few epithelial cells/HPF, absence of casts, calcium oxalate crystals (++), and no ova, trophozoites, mucus, or fungi. These results indicate that the vital indicators are within the normal range.

Vital indicators after treatment

Based on the results of the medical tests conducted after receiving glucosodiene treatment on July 20, 2023, the patient's liver functions were within the normal range. The Serum Glutamic-Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase) level was 32 U/L (up to 40 U/L), and the ASGPT (Alanine Aminotransferase) level was 26 U/L (up to 45 U/L). The ALP (Alkaline Phosphates) level was 164 U/L (normal: 40 U/L-100 U/L), and the AGGT (G-Gutamyl Transpeptidase) level was 23 U/L (normal: 7 U/L-40 U/L)

The kidney functions were also normal, with a serum creatinine level of 0.9 mg/dL (normal: 0.6 mg/dL-1.4 mg/dL) and a blood urea level of 24 mg/dL (normal: 15 mg/dL-45 mg/dL).

The cardiac markers showed a Lactate Dehydrogenase (LDH) level of 458 U/L (normal: 230 U/L-460 U/L).

In the hematological report, the blood picture showed a Hemoglobin (Hgb) level of 12.2 g/dL (reference range: 11.7 g/dL-15.5 g/dL), a Red Blood Cells (RBCs) count of 4.52 x 106 cells/pl, and a Hematocrit (Hct) level of 42.3% (reference range: 35-45%). Other parameters such as Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), Red Cell Distribution Width (RDW), and White Blood Cells (WBCs) count were also within the normal range.

The urinalysis report indicated normal physical examination findings, including volume, colour (amberyellow), odour (aromatic), turbidity (absent), aspect (clear), and deposit (absent). The chemical examination showed an acidic pH of 6.5, negligible trace protein, and absence of sugar, acetone, nitrite, bilirubin, and urobilinogen. Leukocytes and blood were also absent. The microscopic examination revealed a few pus cells, no Red Blood Cells (RBCs), epithelial cells, casts, crystals, ova, trophozoites, mucus, urine artefacts, fungi, or bacteria.

The coagulation profile showed a D-dimer level of 0.42 mg/L (normal: 0-0.50 mg/L), and the serum electrolytes indicated a phosphorous level of 4.58 mg/dL (normal: 2.5 mg/dL-5.0 mg/dL). The venous blood pH was 7.33 (normal: 7.4).

Based on these results, there were no signs of cellular toxicity or impairment in vital body functions after glucosodiene treatment. The liver, kidney, heart, pancreas, blood, blood pH, and urine were all within the normal range, indicating the safety of glucosodiene.

Discussions

This study presents a case report of a 43-year-old female patient with advanced-stage Triple-Negative Breast Cancer (TNBC) stage 3 that had metastasis to the lymph nodes and bones. The patient had previously undergone unsuccessful traditional chemotherapy (4 cycles of Adriamycin and cyclophosphamide every 3 weeks and 12 weekly of Paclitaxel and carboplatin and then go forward directly to surgery with Modified Radical Mastectomy (MRM) then patient suffered from severe pain in the pelvis and legs so admit at the hospital for a bone scan which was revealed many hot active sites uptake refers to osseous metastasis in multiple areas, including the right iliac bone, head and trochanteric area of the right femur, right ischium left acetabulum, and trochanteric area of the left femur.

In-vitro study's discussed the role of high glucose environment at different concentrations of zinc and in the presence or absence of insulin or interleukin 6Ù? the study showed that in the presence of insulin resistance Notably, the expressions of ZnT1, ZnT5, ZIP6, ZIP7, ZIP10, and ZIP14 significantly increased when Zn was increased from 10 M to 100 M under high glucose conditions. Additionally, the relative expression for ZnT1 and ZIP10 reached values well above 20-fold so the glucose environment favours the invasion and metastasis behaviour of triple-negative breast cancer also in the presence of increased zinc [4].

After MRM the patient stopped all medicines and finished all chemotherapy cycles so she thought to take glucosodiene, an alkaline glucose isomer, as a dietary supplement. Then she is followed by our team, The initial five days of treatment with glucosodiene resulted in an improvement in the patient's general health, and able to walk after bed rest for many weeks after surgery and take many analgesics daily to overcome pain, improved of the patient was further confirmed by laboratory tests indicating the health and effectiveness of her vital organs. This suggests that glucosodiene may have a positive impact on the treatment of TNBC. The mechanism of action of glucosodiene in treating TNBC can be attributed to two possibilities. First, glucosodiene may inhibit the GLUT1 receptors, as previous studies have shown that GLUT1 inhibition blocks the growth of RB1-positive triplenegative breast cancer. Second, modifying glucose to an alkaline form may impede glucose metabolism within the tumour, known as the Warburg effect. One century after the discovery of the Warburg effect, in the 1920s that tumours absorbed huge amounts of glucose in comparison to surrounding tissue. Furthermore, even in the presence of oxygen, glucose was digested to create lactate, giving rise to the phrase aerobic glycolysis [5]. As the metabolic pathway is the hallmark of triple-negative breast cancer recently scientists have focused on the role of the metabolic pathway and zinc transporters as studies by TakataniNakase T et al showed that Zinc and its transporters, ZIP6 and ZIP10, are essential for glucose-stimulated motility [6]. These findings provide the first evidence for novel techniques for the detection and treatment of hyperglycemia-related breast cancer. Disrupting the tumor's glucose metabolism could potentially reactivate the p53 enzyme, which is known to influence glucose flux and regulate glycolysis [7]. Furthermore, the alkaline nature of glucosodiene may disrupt the tumor's microenvironment without affecting healthy cells, as evidenced by the safety of vital organ indicators such as the kidney, liver, heart, and blood pH. After 15 days of treatment with glucosodiene, the patient underwent bone scanning, which revealed no presence of active or cold foci. MRI was revealed no suspicious osseous lesions in the pelvic bone. This finding suggests the effectiveness of glucosodiene in stopping and controlling the activity of metastatic triple-negative breast cancer in the advanced stage. But one case is not enough to give the efficacy of this drug and needs more clinical studies regarding metastatic triple-negative breast cancer.

Conclusion

This case study highlights the potential efficacy of glucosodiene as a therapeutic approach for advanced-stage triple-negative breast cancer. The alkaline glucose isomer may interfere with glucose metabolism and reactivate key enzymes involved in tumor control. Further research and clinical trials are warranted to evaluate the effectiveness and safety of glucosodiene as a targeted therapy for TNBC patients.

Abbreviations

TNBC: Triple Negative Breast Cancer

MRM: Modified Radical Mastectomy

Her2: Human epidermal growth factor receptor 2

BMD: Bone Mineral Density

Informed Consent

Before taking this case, information was given to the patient and informed consent was obtained from the patient for follow-up and consent to share the investigations and figures and any required data.

Funding Information

The authors received no financial support for the research and publication of this article.

Competing Interest Declaration

The authors declare that there are no conflicts of interest.

Ethical approval statement or statement of informed consent for case studies

This case was conducted in accordance with the declaration of Helsinki and meets the care guidelines criteria informed consent was obtained from the patient for follow up including permission for publication of all photographs, lab, and images herein. Trial registration details: NCT05957939.

References

1. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J clin investig. 2011;121:2750-2767.

   [Google Scholar]

2. Akl MM. Targeting Cancerous Tumors through their Metabolic Activity via Glucose Receptors in the Tumor; Known as the Alkaline Glucosodiene Molecules Theory. Clin Exp Cancer Res Ther.

   [Google Scholar] [Crossref]

3. Akl MM, Abou El Naga AM. Toxic chemotherapeutic nutrition of cancer cells by alkaline glucosodiene molecules via targeting metabolic of cancerous tumors: a promising theory for cancer treatment. Cancer Adv. 2023;6:23010.

   [Google Scholar] [Crossref]

4. Ruz M, Andrews-Guzmán M, Arredondo-Olguín M. Modulation of Zinc Transporter Expressions by Additional Zinc in C2C12 Cells Cultured in a High Glucose Environment and in the Presence of Insulin or Interleukin-6. Biol Trace Elem Res. 2023;201:3428-37.

   [Google Scholar] [Crossref]

5. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells?. Trends biochem sci. 2016;41:211-218.

   [Google Scholar] [Crossref]

6. Takatani-Nakase T, Matsui C, Maeda S, Kawahara S, Takahashi K. High glucose level promotes migration behavior of breast cancer cells through zinc and its transporters. PLoS One. 2014;9:e90136.

   [Google Scholar] [Crossref]

7. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126:107-120.

   [Google Scholar] [Crossref]