Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms

Simple Summary Cancer, which is a major health problem, is a complex disease. Currently, the main treatment methods are surgery, chemotherapy, radiotherapy and biological therapies. The latter include hormonal therapies, inhibitors of growth-promoting tyrosine kinase enzymes, and immunotherapy which aims to activate the immune system to destroy tumors. Whilst all these methods work, efficacy is often limited in time (with tumors gradually becoming resistant to treatment). Furthermore, undesirable side effects, which can seriously curtail quality of life, are common. Consequently, in addition to new treatment modalities constantly being developed, it is even more expedient to make existing therapies more effective by combining them with each other or with other agents. Here, we evaluate the evidence for the effectiveness of combining conventional cancer treatments with modulators of ionic mechanisms, mainly channels that permeate sodium, calcium and potassium. We conclude, in every case, that such combinations can produce improved outcome by making given treatments more effective and reducing the undesirable side effects. In addition, ionic modulators by themselves can exert anti-cancer effects. Abstract Cancer is a global health problem that 1 in 2–3 people can expect to experience during their lifetime. Several different modalities exist for cancer management, but all of these suffer from significant shortcomings in both diagnosis and therapy. Apart from developing completely new therapies, a viable way forward is to improve the efficacy of the existing modalities. One way is to combine these with each other or with other complementary approaches. An emerging latter approach is derived from ionic mechanisms, mainly ion channels and exchangers. We evaluate the evidence for this systematically for the main treatment methods: surgery, chemotherapy, radiotherapy and targeted therapies (including monoclonal antibodies, steroid hormones, tyrosine kinase inhibitors and immunotherapy). In surgery, the possible systemic use of local anesthetics to suppress subsequent relapse is still being discussed. For all the other methods, there is significant positive evidence for several cancers and a range of modulators of ionic mechanisms. This applies also to some of the undesirable side effects of the treatments. In chemotherapy, for example, there is evidence for co-treatment with modulators of the potassium channel (Kv11.1), pH regulation (sodium–hydrogen exchanger) and Na+-K+-ATPase (digoxin). Voltage-gated sodium channels, shown previously to promote metastasis, appear to be particularly useful for co-targeting with inhibitors of tyrosine kinases, especially epidermal growth factor. It is concluded that combining current orthodox treatment modalities with modulators of ionic mechanisms can produce beneficial effects including (i) making the treatment more effective, e.g., by lowering doses; (ii) avoiding the onset of resistance to therapy; (iii) reducing undesirable side effects. However, in many cases, prospective clinical trials are needed to put the findings firmly into clinical context.