Alcohol and Cancer: Mechanisms and Therapies

Anuradha Ratna, Pranoti Mandrekar, Anuradha Ratna, Pranoti Mandrekar

Abstract

Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti-tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects of alcohol with tumor progression and metastasis. The influence of alcohol on the host immune system and the development of possible effective immunotherapy for cancer in alcoholics are also discussed here. The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease. This review provides insights into cancer pathogenesis in alcoholics, alcohol and immune interactions in different cancers, and scope and future of targeted immunotherapeutic modalities in patients with alcohol abuse.

Keywords: alcohol; animal models; cancer risk; immunosuppression; immunotherapy; metabolism.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pathways of ethanol metabolism. Ethanol is oxidized mainly by cytosolic alcohol dehydrogenase (ADH) to acetaldehyde. Acetaldehyde then enters the mitochondria where it is oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH). Another major pathway of ethanol metabolism includes its oxidation in microsomes by cytochrome P450 2E1 (CYP2E1) enzyme and requires nicotinamide adenine dinucleotide phosphate (NADPH) instead of nicotinamide adenine dinucleotide (NAD+) as for ADH. Reactive oxygen species (ROS) are formed due to alcohol metabolism by CYP2E1 and the re-oxidation of NADH in the mitochondria. A catalase-mediated reaction in the peroxisomes is considered a minor metabolic pathway of alcohol metabolism.
Figure 2
Figure 2
Various mechanisms by which alcohol may affect carcinogenesis. Ethanol is oxidized to acetaldehyde by ADH, which acts as a carcinogen and binds to DNA. This metabolism is modified by polymorphisms or mutations in the genes encoding metabolizing enzymes. Acetaldehyde can form hybrid-adducts with reactive residues (e.g., malondialdehyde adduct) acting on proteins, mediating lipid peroxidation and nucleic acid oxidation. Excessive alcohol consumption leads to the induction of CYP2E1 pathway and may indirectly contribute to acetaldehyde development and ROS production. Excessive alcohol enhances catabolism of retinoic acid by alcohol-induced CYP2E1. The interaction of retinoids with different signaling pathways, including estrogen signaling, may favor proliferation and malignant transformation of pre-cancerous cells. Chronic ethanol intake is also associated with the failure of immune surveillance of tumor cells.

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