Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer
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Valentina Belli1, Vincenzo Sforza1, Claudia Cardone1, Erika Martinelli1, Giusi Barra2, Nunzia Matrone1, Stefania Napolitano1, Floriana Morgillo1, Concetta Tuccillo3, Alessandro Federico3, Marcello Dallio3, Carmelina Loguercio3, Antonietta Gerarda Gravina3, Raffaele De Palma2, Fortunato Ciardiello1 and Teresa Troiani1
1Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
2Medicina Interna, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
3Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
Keywords: metastatic colorectal cancer (mCRC), regorafenib, silybin, reactive oxygen species (ROS)
Received: May 31, 2017 Accepted: July 25, 2017 Published: August 07, 2017
Purpose: Regorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed.
Experimental design: We have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells. Furthermore, we have prospectively treated a cohort of 22 refractory mCRC patients with regorafenib plus silybin.
Results: Treatment with regorafenib determined a dose-dependent growth inhibition whereas treatment with silybin had no anti-proliferative effects among all cancer cells tested. The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway. Moreover, combined treatment with regorafenib and silybin increased the production of reactive oxygen species levels within cells. In an exploratory proof of concept clinical study in a cohort of 22 mCRC patients after failure of all standard therapies, the clinical activity of regorafenib in combination with silybin was assessed. A median progression-free survival of 10.0 months and a median overall survival of 17.6 months were observed in these patients. These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib. Moreover, due to its anti-oxidative properties, silybin could protect patients from drug-induced liver damages, allowing to continue an effective anti-cancer therapy.
Conclusions: The present study suggests that silybin in combination with regorafenib is a promising strategy for treatment of metastatic colorectal patients.
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