The SCD1 Inhibitor Aramchol, Regorafenib, and Metformin Combine to Kill Uveal Melanoma Cells

Mar 31, 2026

A discussion of how aramchol, regorafenib, and metformin work together to kill uveal melanoma and cholangiocarcinoma cells. They highlight a triple-drug boost in autophagosome formation and autophagic flux. The conversation touches on molecular contributors like BID and autophagy genes. They also consider aramchol actions beyond SCD1 and potential for treating liver metastases.

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INSIGHT

Three-Drug Combination Enhances Tumor Cell Killing

Aramchol, regorafenib, and metformin synergize to increase killing of patient-derived uveal melanoma and cholangiocarcinoma cells.
The strongest cytotoxic effect occurred when metformin was added to the aramchol plus regorafenib combination in cultured UM and LD-1 cells.

INSIGHT

Enhanced Autophagic Flux Drives Cell Death

The three-drug treatment increases autophagosome formation and autophagic flux, linking enhanced macroautophagy to cell death.
Knockdown of Beclin1, ATG5, or LAMP2 reduced autophagosome/autolysosome formation and lowered cell killing, showing autophagy dependency.

INSIGHT

BID Links Death-Receptor Signaling To Killing

BID contributes to the lethal response, indicating death-receptor signaling complements autophagy in killing tumor cells.
The authors describe a multifactorial mechanism involving both macroautophagy and death-receptor pathways in treated UM cells.

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BUFFALO, NY – March 31, 2026 – A new #research paper was #published in Volume 17 of Oncotarget on March 27, 2026, titled “The SCD1 inhibitor aramchol interacts with regorafenib and metformin to kill tumor cells.” Led by Michael R. Booth, Laurence Booth, and Jane L. Roberts from Virginia Commonwealth University, with corresponding author Paul Dent from the same institution and John M. Kirkwood from the University of Pittsburgh Cancer Institute, the study examines how aramchol interacts with regorafenib and metformin to kill tumor cells, particularly patient-derived uveal melanoma (UM) cells and cholangiocarcinoma cells. The authors report that aramchol, regorafenib, and metformin interact to enhance tumor cell killing, with the strongest effects seen when metformin is added to aramchol plus regorafenib. In patient-derived UM cells and LD-1 cholangiocarcinoma cells, the three-drug combination increased autophagosome formation and autophagic flux, while knockdown of Beclin1, ATG5, or LAMP2 reduced autophagosome and autolysosome formation and lowered cell killing. The study also found that BID contributes to the lethal response, supporting a multifactorial mechanism involving macroautophagy and death-receptor signaling. “Our data demonstrates that UM cells are killed by treatment with aramchol plus regorafenib plus metformin via enhanced autophagic flux and that this combination may have the potential to control UM tumors that have metastasized to the liver.” The authors also note that while SCD1 knockdown increased baseline tumor cell death, it did not replicate the full anticancer effects of aramchol, suggesting additional molecular targets contribute to its activity. They emphasize the need for further in vivo studies to evaluate the therapeutic potential of this combination in metastatic uveal melanoma, particularly in liver-targeted disease. DOI - https://doi.org/10.18632/oncotarget.28861 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Abstract video - https://www.youtube.com/watch?v=lmX_c2e_-HY Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28861 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, macroautophagy, ER stress, aramchol, regorafenib, BID To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM