# Pro-Tumorigenic Effect of Continuous Cromolyn Treatment in Bladder Cancer

## TL;DR

This study shows that continuous cromolyn treatment promotes bladder cancer growth in mice by inhibiting mast cell activity and suppressing immune responses.

## Contribution

The study reveals that cromolyn, known as a mast cell stabilizer, can have pro-tumorigenic effects when administered continuously in bladder cancer models.

## Key findings

- Continuous cromolyn treatment increased tumor burden by suppressing immune cell recruitment and apoptotic pathways.
- The pro-tumorigenic effect was observed even in mast cell-deficient mice, suggesting mast cell degranulation inhibition is key.
- Therapeutic cromolyn treatment downregulated angiogenesis genes and upregulated cytotoxic immune cell activity.

## Abstract

Globally, bladder cancer is the sixth most frequently diagnosed cancer among men. Despite the increasing availability of immunomodulatory treatments for bladder cancer, the survival rates are still low, which calls for potential new drug-repurposing targets. This study aimed to investigate the effects of cromolyn, a mast cell (MC) stabilizer in allergic reactions, on a subcutaneous tumor model with a syngeneic mouse MB49 bladder cancer cell line. A concentration of 50 mg/kg of cromolyn was daily administered intraperitoneally in a 4-day therapeutic protocol to mice with established tumors and in a continuous 11-day protocol which started one day prior to the subcutaneous injection of tumor cells. Therapeutic treatment demonstrated a marked downregulation of genes related to angiogenesis and upregulation of genes related to cytotoxic T-cell and NK cell activity. Conversely, continuous cromolyn treatment suppressed genes involved in immune cell recruitment and activation, as well as apoptotic and necroptotic pathways, leading to a greater tumor burden (+142.4 mg [95CI + 28.42, +256.4], p = 0.0158). The same pro-tumorigenic effect was found in mast cell-deficient mice (KitW-sh/W-sh + 301.7 mg [95CI + 87.99, 515.4], p = 0.0079; Cpa3Cre/+ +107.2 mg [95CI − 39.37, +253.57], p = 0.1423), indicating that continuous cromolyn treatment mostly acts through the inhibition of mast cell degranulation. In summary, our results demonstrate the distinct effects of cromolyn on tumor progression, which depend on the protocol of cromolyn administration.