Abstract
The coexistence of cancer and other concomitant diseases is very frequent and has substantial implications for treatment decisions and outcomes. Beta-blockers, agents that block the beta-adrenergic receptors, have been related also to cancers. In the model of multicellular spheroids formed by colorectal cancer cells we described a crosstalk between beta-blockade by propranolol and tumour microenvironment. Non-selective beta-blocker propranolol decreased ability of tumour cells to adapt to hypoxia by reducing levels of HIF1α and carbonic anhydrase IX in 3D spheroids. We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, thus mediating decrease of CA IX expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA). Moreover, the inhibition of β-adrenoreceptors by propranolol enhanced apoptosis, decreased number of mitochondria and lowered the amount of proteins involved in oxidative phosphorylation (V-ATP5A, IV-COX2, III-UQCRC2, II-SDHB, I-NDUFB8). Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids. To choose the right treatment strategy, it is extremely important to know how the treatment of concomitant diseases affects the superior microenvironment that is directly related to the efficiency of anti-cancer therapy
Highlights
The presence of co-existing diseases and their often chronic treatment can significantly affect the proliferation, growth and metastasis of the tumour itself
We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, mediating decrease of carbonic anhydrase IX (CA IX) expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA)
Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids
Summary
The presence of co-existing diseases and their often chronic treatment can significantly affect the proliferation, growth and metastasis of the tumour itself. The evidence of the effect of comorbidities and their treatment on the outcome of anticancer therapy is missing, partly due to the lack of clinical studies from which such patients are often excluded [4]. Cancer patients represent a population predisposed to the development of many comorbidities that affect the overall outcome [5]. Epidemiological studies have shown that in the US four out of ten patients diagnosed with cancer (older than 65 years) suffer from at least one other chronic disease and 15% have two or more comorbidities [7]. The evidence of the effect of comorbidities and their treatment on the outcome of anticancer treatment is missing, due to the lack of clinical studies from which such patients are often excluded [4]. The chronic treatment of comorbidities and the burden of comorbid diseases in relation to treatment and outcomes of cancer have been seldomly described
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