Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H plus efflux

Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane perme-abilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H+ efflux that requires P2RX4-mediated lysosomal Ca2+ release and precedes the lysosomal membrane perme-abilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription fac-tor. Moreover, CAD-induced lysosomal H+ efflux sensitizes cancer cells to apoptosis induced by STAT3 in-hibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H+ efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy.

Automated summary

Commonly used antihistamines and other cationic amphiphilic drugs (CADs) have emerged as potential cancer drugs due to their ability to alter lysosomal pH and inhibit STAT3 signaling, leading to cancer cell apoptosis and inhibition of tumor growth. The rapid elevation of lysosomal pH induced by CADs is caused by lysosomal H+ efflux mediated by P2RX4 and precedes lysosomal membrane permeabilization. These findings highlight the anticancer mechanisms of CADs and support their repurposing as cheap and safe cancer drugs, especially in combination with STAT3 inhibition.