In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101.

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor and mainly affects children and adolescents. The OS five-year survival rate remains very low. Thus, novel therapeutic protocols for the treatment of OS are needed. Several approaches targeting deregulated signaling pathways have been proposed. The antitumoral effects of polyphenols, which are naturally occurring compounds with potent antioxidant and anti-inflammatory activity, have been investigated in different tumors. Gossypol, which is a natural polyphenolic aldehyde isolated from the seeds of the cotton plant, has been shown to exert antitumoral activity in leukemia and lymphoma and in breast, head and neck, colon and prostate cancers. Therefore, in this study, we evaluated the effect of AT-101, which is the (-) enantiomer and more active form of gossypol, on the growth of human and murine OS cells in vitro and in vivo. Several clinical trials employing AT-101 have been performed, and some clinical trials are ongoing. Our results showed for the first time that AT-101 significantly inhibits OS cell growth in a dose- and time-dependent manner, inducing apoptosis and necrosis and partially activating autophagy. Our results demonstrated that AT-101 inhibits prosurvival signaling pathways depending on Akt, p38 MAPK and JNK. In addition, treatment with AT-101 increases the survival of OS-bearing mice. Overall, these results suggest that AT-101 is a candidate chemo-supportive molecule for the development of novel chemotherapeutic protocols for the treatment of OS.

• Authors: Laura Masuelli, Monica Benvenuto, Valerio Izzi, Erika Zago, Rosanna Mattera, Bruna Cerbelli, Vito Potenza, Sara Fazi, Sara Ciuffa, Ilaria Tresoldi, Enrico Lucarelli, Andrea Modesti, Roberto Bei
• Journal: Investigational new drugs (Invest New Drugs) Vol. 38 Issue 3 Pg. 675-689 (06 2020) ISSN: 1573-0646 [Electronic] United States
• PMID: 31264066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Polyphenols
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• p38 Mitogen-Activated Protein Kinases
• Gossypol
• gossypol acetic acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Bone Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gossypol (analogs & derivatives, pharmacology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred BALB C
• Osteosarcoma (drug therapy, metabolism)
• Polyphenols (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)