Cancer remains one of the most challenging diseases to treat, prompting continuous research into novel therapeutic strategies. Citrate, a key metabolite in cellular energy production, has emerged as a potential anti-cancer agent due to its multifaceted mechanisms of action against tumor cells. This article delves into the various anti-cancer properties of citrate and highlights clinical observations supporting its potential therapeutic role.
Inhibition of Glycolysis (Warburg Effect)
Cancer cells predominantly rely on glycolysis for energy production, even in the presence of oxygen—a phenomenon known as the Warburg effect. Citrate disrupts this metabolic reprogramming by inhibiting key glycolytic enzymes such as phosphofructokinase-1 (PFK1), phosphofructokinase-2 (PFK2), glucose transporter 1 (Glut1), and hexokinase 2 (HK2). Additionally, citrate reduces the expression of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that promotes glycolysis under low oxygen conditions. By targeting these enzymes and regulatory proteins, citrate limits the energy supply crucial for cancer cell proliferation.
Induction of Apoptosis
Apoptosis, or programmed cell death, is a natural mechanism to eliminate damaged or unwanted cells. Citrate induces apoptosis in cancer cells via mitochondrial pathways by activating caspase-3 and caspase-9—key enzymes that execute the apoptotic process. It also downregulates anti-apoptotic proteins like B-cell lymphoma 2 (BCL2), tipping the balance towards cell death. Furthermore, citrate suppresses the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)/AKT/mTOR signaling pathway by decreasing intracellular calcium (Ca²⁺) levels, essential for cell survival and growth.
Induction of Ferroptosis
Ferroptosis is a form of regulated cell death characterized by iron accumulation and lipid peroxidation. Citrate promotes ferroptosis by increasing intracellular ferrous iron (Fe²⁺) content, enhancing lipid peroxidation (LPO), and elevating levels of malondialdehyde (MDA) and reactive oxygen species (ROS). It also stimulates ferritinophagy via nuclear receptor coactivator 4 (NCOA4), leading to ferritin degradation and further increasing free iron levels. This cascade culminates in ferroptotic cell death, offering another avenue through which citrate can eliminate cancer cells.
Chelation of Intracellular Ca²⁺
Calcium ions are pivotal in various cellular processes, including mitochondrial function and energy production. Citrate acts as a chelating agent, reducing cytosolic and mitochondrial Ca²⁺ levels. This reduction impairs mitochondrial function, disrupts oxidative phosphorylation, and increases ROS production. The resultant energy deficit and oxidative stress collectively drive cancer cells toward cell death.
Suppression of CAMKK2/AMPK Pathway
The CAMKK2/AMP-activated protein kinase (AMPK) pathway is integral to cellular energy homeostasis. Citrate inhibits this signaling cascade, reducing mitochondrial Ca²⁺ uptake and dampening energy metabolism. By suppressing this pathway, citrate contributes to apoptosis and ferroptosis in cancer cells.
Metabolic Reprogramming
Cancer cells undergo metabolic reprogramming to support their rapid growth and survival. Citrate interferes with this process by increasing lipotoxicity through enhanced phospholipid biosynthesis. It disrupts tricarboxylic acid (TCA) cycle intermediates like alpha-ketoglutarate and succinate, impairing energy production and biosynthetic pathways necessary for cancer cell survival.
Alkalinizing the Tumor Microenvironment (TME)
The tumor microenvironment is often acidic due to the high metabolic rate of cancer cells. Citrate acts as a buffering agent, neutralizing the acidic pH of the TME. This alkalinization can impair cancer cell proliferation, local invasion, and metastasis. Additionally, a neutral pH enhances immune cell activity, potentially improving the body’s natural anti-tumor responses.
Inhibition of Tumor Growth and Spread
Citrate effectively suppresses tumor growth across various cancer models through the abovementioned mechanisms. Citrate demonstrates a desirable degree of selectivity in cancer therapy by targeting cancer-specific pathways while sparing normal cells.
Improved Chemotherapy Sensitivity
Resistance to chemotherapy is a significant hurdle in cancer treatment. Citrate has been shown to enhance the efficacy of chemotherapeutic agents like carboplatin, gemcitabine, and cisplatin. Citrate may improve treatment outcomes by sensitizing cancer cells and overcoming drug resistance mechanisms.
Clinical Observations by Dr. Alberto Halabe Bucay
Dr. Alberto Halabe Bucay, a Mexican physician and medical writer, has reported clinical observations supporting the anti-cancer potential of citrate. Between 2009 and 2016, he published cases of 12 patients with various types of cancer who showed significant improvement solely with oral citric acid treatment. Once ingested, citric acid undergoes an ionization process, losing a hydrogen ion (H⁺) and becoming citrate.
The cases included patients with medullary thyroid cancer, peritoneal mesothelioma, myeloid leukemia, Hürthle thyroid tumor, endocrine hepatic tumor, esophageal cancer, multiple myeloma, glioblastoma multiforme, pancreatic cancer, non-Hodgkin’s lymphoma, bladder cancer, and breast cancer. While these observations are intriguing, it is essential to note that more extensive clinical trials are necessary to validate citrate’s efficacy and safety as a cancer treatment.
Conclusion
Citrate exhibits multiple anti-cancer mechanisms, ranging from metabolic disruption to induction of cell death pathways like apoptosis and ferroptosis. Its ability to inhibit tumor growth, enhance chemotherapy sensitivity, and modulate the tumor microenvironment positions it as a promising candidate for cancer therapy. However, further research, including clinical trials, is essential to fully understand its potential and translate these findings into standardized treatments. As the scientific community continues to explore citrate’s properties, it may pave the way for more effective and less toxic cancer therapies.
References
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- Halabe Bucay A. Case Report: A Patient With Pancreatic Cancer Who Improved After the Treatment with Citric Acid That She Received. Indian J Appl Res. 2015 Dec;5(12):392.
- Icard P, Coquerel A, Wu Z, Gligorov J, Fuks D, Fournel L, Lincet H, Simula L. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update. Int J Mol Sci. 2021 Jun 19;22(12):6587.
- Ren JG, Seth P, Ye H, Guo K, Hanai JI, Husain Z, Sukhatme VP. Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway. Sci Rep. 2017 Jul 3;7(1):4537.
- Yin X, Chen W, Ao X, Xu L, Cao J, Huang T, Liang J, Hu J, Liu J, Wang X, Li W, Zhou M, He L, Guo Z. Sodium citrate pretreatment enhances CAR-T cell persistence and anti-tumor efficacy through inhibition of calcium signaling. Front Immunol. 2025 Mar 17;16:1540754.
