Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells

Abstract

Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.

Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

“…The synergistic effects resulted also in increased T cell-mediated immune responses and decreased PGE2 production ( 245 ). In experimental models, we showed that aspirin or the beta-blocker agent atenolol can augment the activity of metformin, a biguanide largely employed in type 2 diabetes management and that have been associated to reduced risk of developing diverse cancers, including breast cancers (Figure 4 ), targeting both neoplastic cells and the TME ( 246 , 247 ). Metformin and phenformin affect the angiogenesis pathway ( 248 – 250 ) and modulate the immune response and the microbiome ( 251 , 252 ).…”

Metformin sensitizes lung cancer cells to treatment by the tyrosine kinase inhibitor erlotinib

“…This is due to the ability of Met to indirectly activate AMP-activated protein kinase (AMPK) by inhibiting oxidative phosphorylation in liver cells [ 16 ]. Recently Met class drugs have been shown to possess anticancer properties [ 17 – 19 ], while the mechanisms were controversial. Recent research demonstrated that Met inhibits cell growth by attenuating mitochondrial respiratory capacity, which restrains the transit of RagA-RagC GTPase heterodimer through nuclear pore complex (NPC).…”

Propranolol and breast cancer—a work in progress

“…Of course there are many other beta blockers in widespread clinical use, both non-selective (for example carvedilol) and selective (examples include β1-selective atenolol). While the majority of preclinical studies have focused on propranolol there is also some evidence for anticancer effects for carvedilol [ 28 , 29 ], atenolol [ 30 ] and others. These drugs vary by the degree of beta adrenergic receptor selectivity and range of off-target effects, and it remains to be seen to what extent these impact the anticancer potential of these drugs.…”