# Clofazimine Treatment Modulates Key Non-Coding RNAs Associated with Tumor Progression and Drug Resistance in Lethal Prostate Cancer

## TL;DR

Clofazimine, a drug for leprosy, shows promise in treating lethal prostate cancer by targeting non-coding RNAs linked to tumor progression and drug resistance.

## Contribution

The study demonstrates that clofazimine modulates non-coding RNAs like MALAT1 and NEAT1 in prostate cancer, offering a novel therapeutic strategy.

## Key findings

- Clofazimine reduces cancer stemness markers like ALDH activity and metastatic potential in prostate cancer cells.
- Clofazimine treatment is associated with increased apoptosis and mitochondrial dysfunction in cancer cells.
- Clofazimine modulates non-coding RNAs MALAT1 and NEAT1, which are linked to tumor progression and drug resistance.

## Abstract

Metastatic castration-resistant prostate cancer/PCa (mCRPC) is a clinically advanced form of PCa that is associated with increased aggressiveness, cancer stemness, morbidity, and the risk of developing resistance to taxanes, currently the first-line chemotherapy for mCRPC. Clofazimine (CLF) is a potential immunomodulator drug that is FDA-approved for the treatment of leprosy. Recently, using in vitro, in vivo, and ex vivo models, we established the efficacy of CLF in chronic myeloid leukemia and multiple myeloma. Here, we demonstrate that CLF is effective as a single agent and in combination with taxanes in a panel of cell lines representing the diversity of CRPC patients. Using a microfluidic assay, we showed the impact of CLF on cancer cell migration and metastatic potential. Further, we also found that CLF reduces ALDH activity—a marker for cancer ‘stem-like’ cells (CSCs), a subtype of cancer cells with self-renewal and differentiation capacities (epithelial-to-mesenchymal transdifferentiation/EMT). Bulk and single-cell RNAseq followed by functional validation and in silico analysis showed that CLF treatment is associated with apoptosis, ER stress, oxidative phosphorylation, and mitochondrial dysfunction. Most importantly, CLF modulates the expression of several non-coding RNAs, including MALAT1 and NEAT1, that are linked to tumor cell proliferation, cell migration, and drug resistance.