Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer

Abstract

Research on the neurobiology of cancer, which lies at the border of neuroscience and oncology, has elucidated the mechanisms and pathways that enable the nervous system to modulate processes associated with cancer initiation and progression. This research has also shown that several drugs which modulate interactions between the nervous system and the tumor micro- and macroenvironments significantly reduced the progression of cancer in animal models. Encouraging results were also provided by prospective clinical trials investigating the effect of drugs that reduce adrenergic signaling on the course of cancer in oncological patients. Moreover, it has been shown that reducing adrenergic signaling might also reduce the incidence of cancer in animal models, as well as in humans. However, even if many experimental and clinical findings have confirmed the preventive and therapeutic potential of drugs that reduce the stimulatory effect of the nervous system on processes related to cancer initiation and progression, several questions remain unanswered. Therefore, the aim of this review is to critically evaluate the efficiency of these drugs and to discuss questions that need to be answered before their introduction into conventional cancer treatment and prevention.

Keywords: adrenergic; antibodies against nerve growth factor; aspirin; cancer; electroceuticals; local anesthetics; metformin; neurobiology of cancer; propranolol; β-blockers.

Figure 1

Experimental and clinical studies have shown that propranolol affects all hallmarks of cancer defined by Hanahan and Weinberg [52]. Even if these studies created a basis for potentially employing propranolol in cancer treatment and prevention, further studies are necessary to determine its efficacy in various human cancers.

Figure 2

Dosage of propranolol used to prevent perioperative and postoperative metastases in a clinical study by Hiller, et al. [96]. At the beginning (day −7), patients received 40 mg of propranolol twice a day; from day −4, they received 80 mg twice a day, and after the operation, the dose was gradually reduced. ext—day of tumor tissue extirpation.

Figure 3

Schematic depiction of the vicious cycle created between nerves and cancer cells. Nerves innervating cancer tissue release neurotransmitters (e.g., acetylcholine (Ach), norepinephrine (NE), neuropeptide Y (NPY)) that stimulate tumor growth. The more cancer cells, the more released molecules, inducing the ingrowth of new axons (e.g., nerve growth factor, NGF). Therefore, administration of antibodies against NGF or suppression of the release of other molecules related to neoaxoneogenesis might be useful in reducing cancer growth. Modified according to Venkatesh and Monje [123].

Figure 4

Schematic depiction of the mechanisms involved in the development of cancer cachexia. In addition to peripheral mechanisms, hypothalamic inflammation induced by cytokines and other factors synthesized in the tumor microenvironment and peripheral tissues is involved in the development of cachexia. Hypothalamic inflammation disrupts regulation of food intake and increases energy expenditure. Therefore, drugs such as aspirin or metformin might directly or indirectly reduce hypothalamic inflammation and could be useful in the treatment of cancer anorexia and cachexia. Modified according to Argiles, et al. [149]. NEFA—non-essential fatty acids; TAGs—triacylglycerols.