Are dihydropyridines a potential cure for rhabdomyosarcoma?

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, poses a significant challenge in pediatric oncology due to its aggressive metastatic behavior and drug resistance. Despite many advancements, RMS, especially in its advanced stages, lacks effective therapeutic strategies. The rarity of this disease (approximately 350 cases per year in North America) does not help in attracting pharmaceutical companies to focus on developing treatments for it on a large scale.

In a recent collaborative study, researchers from the Children’s Cancer Therapy Development Institute, the Genomics Institute of the Novartis Research Foundation, and ApconiX performed a large-scale screen of 640,000 compounds developed by Novartis as the Academic Collaboration Set (ACS), aiming to identify new potential drugs for treating rhabdomyosarcoma. This massive screen identified dihydropyridines (DHPs), a class of anti-hypertensives, as lead candidates.

Out of 15 dihydropyridine compounds tested against four RMS cell lines, azelnidipine was selected as the lead compound due to its consistent anti-tumor cell activity. Importantly, the anti-tumor activity of azelnidipine in vitro was also paralleled by studies in vivo.

Unexpectedly, the effect of DHPs on RMS was not through the expected target, the L-type voltage-gated calcium channel (VGCC), suggesting a non-traditional, RMS-specific mechanism. This finding was supported by various tests and assays, including patch-clamp experiments performed at ApconiX using the Patchliner automated patch-clamp system from Nanion. Albeit all the DHPs tested effectively inhibited L-type calcium channels, this effect did not account for their anti-tumor activity, as non-dihydropyridine calcium channel antagonists had no cell growth inhibitory effect on the rhabdomyosarcoma cell lines.

Although the exact mechanism of the anti-rhabdomyosarcoma activity of DHPs was not uncovered in this study, these findings provide the basis for future medicinal chemistry programs to develop dihydropyridine derivatives for the treatment of rhabdomyosarcoma.

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