KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)

Glaser, Felix; Hundehege, Petra; Bulk, Etmar; Todesca, Luca Matteo; Schimmelpfennig, Sandra; Nass, Elke; Budde, Thomas; Meuth, Sven G.; Schwab, Albrecht

doi:10.1038/s41598-021-97406-0

Cited by 20 publications

(17 citation statements)

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“…Besides Tram-34 used herein for the functional analysis of acute IK modulation in multiple ex vivo BC cell "treatment" scenarios, Senicapoc, a selective inhibitor of IK, was introduced in clinical trials and was previously tested as a safe and well tolerated drug [87]. To the best of our knowledge, it was not assessed whether this clinical candidate inhibits BC development in an IK-dependent manner, while promising anti-cancer effects attributed to Senicapoc derive from cellular and pre-clinical studies on melanoma, glioma, and non-small cell lung cancer [87][88][89][90].…”

Section: Discussionmentioning

confidence: 99%

IKCa channels control breast cancer metabolism including AMPK-driven autophagy

et al. 2022

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Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K+- and Ca2+- homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca2+- and K+-dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy.

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Section: Discussionmentioning

confidence: 99%

IKCa channels control breast cancer metabolism including AMPK-driven autophagy

et al. 2022

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“…KCNN4 also plays a role in chemoresistance in CRC, and the KCa3.1 activator SKA-31 and Kv11.1 inhibitor E4031 have synergistic effects with cisplatin in causing apoptosis and inhibiting proliferation, helping to improve the efficacy of cisplatin and overcome cisplatin resistance in CRC ( 102 ). KCa3.1 channel blockers can increase the sensitivity of NSCLC cells to erlotinib and overcome resistance ( 103 ). Increased expression of KCa3.1 channels by radiation can suppress the pro-invasive phenotype induced by counteracting radiation in tumor cells and inhibit tumor resistance after radiation therapy in GBM patients ( 104 ).…”

Section: Role Of Potassium Channel In Diagnosis and Treatment Of Tumormentioning

confidence: 99%

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

Tian

Zhao

et al. 2023

Front. Oncol.

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In recent years, the role of potassium channels in tumors has been intensively studied. Potassium channel proteins are widely involved in various physiological and pathological processes of cells. The expression and dysfunction of potassium channels are closely related to tumor progression. Potassium channel blockers or activators present antitumor effects by directly inhibiting tumor growth or enhancing the potency of classical antitumor agents in combination therapy. This article reviews the mechanisms by which potassium channels contribute to tumor development in various tumors in recent years, introduces the potential of potassium channels as diagnostic targets and therapeutic means for tumors, and provides further ideas for the proper individualized treatment of tumors.

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“…Another TKI used commonly against NSCLC and pancreatic cancer is erlotinib (Tarceva). Similar to gefinitib, the effectiveness of erlotinib could be enhanced by coupling with blockers of ion channels including K Ca 3.1 [ 100 ] and ANO9/TMEM16J [ 101 ].…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

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

Djamgoz

2022

Cancers

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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.

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KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)

Cited by 20 publications

References 50 publications

IKCa channels control breast cancer metabolism including AMPK-driven autophagy

IKCa channels control breast cancer metabolism including AMPK-driven autophagy

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

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

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