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

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.

Combination Therapy with a Bispecific Antibody Targeting the hERG1/β1 Integrin Complex and Gemcitabine in Pancreatic Ductal Adenocarcinoma

“…Finally, given the excellent imaging data provided in this study, the scDb-hERG1-β1 can be exploited (e.g., in PA imaging) to identify patients that could benefit from the combination of the scDb-hERG1-β1 with chemotherapeutic drugs. Overall, our data pave the way for improving the therapy of PDAC, and possibly other cancers, by combining chemotherapy with ion channel modulators [ 54 ].…”

Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells

“…This study aimed to address the role of K Ca 3.1 channels in EGFR-TKI resistance in NSCLC. Growth factor receptors like EGFR and ion channels often functionally cooperate in cancer cells so that anti-cancer effects of TKIs can be potentiated by co-treatment with ion channel modulators 25,26 . Indeed, frequently therapy resistance is related to overexpression or reduction of K + channel expression 27 .…”

Synergistic Chemo-Photothermal Therapy of Breast Cancer Based on Mesoporous Polydopamine Nanoparticles Decorated with Atovaquone

“…They can reverse or inhibit the biochemical metabolic process of cancer cells when reaching a certain concentration, thereby interfering with the cellular division of cancer cells. However, common chemotherapy can cause nonspecific systemic dispersion of antineoplastic agents, resulting in the low concentration of drugs reaching the intended target and severe side effects. , Therefore, it is essential to develop a more specific chemo-drug delivery system.…”

“…However, common chemotherapy can cause nonspecific systemic dispersion of antineoplastic agents, resulting in the low concentration of drugs reaching the intended target and severe side effects. 10,11 Therefore, it is essential to develop a more specific chemo-drug delivery system. Atovaquone (ATO), an antiprotozoal drug, has shown strong anticancer activities against primary breast cancer, even paclitaxel-resistant and triple-negative breast tumors.…”