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Article

Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells

by
Manuela Piazzi
1,2,†,
Alberto Bavelloni
3,†,
Vittoria Cenni
1,2,
Sara Salucci
4,
Anna Bartoletti Stella
5,
Enrica Tomassini
5,
Katia Scotlandi
3,
William L. Blalock
1,2,* and
Irene Faenza
4,*
1
Istituto di Genetica Molecolare ‘‘Luigi Luca Cavalli-Sforza’’, Consiglio Nazionale delle Ricerca (IGM-CNR), 40136 Bologna, Italy
2
IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
3
Laboratorio di Oncologia Sperimentale, IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
4
Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, 40138 Bologna, Italy
5
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Università di Bologna, 40138 Bologna, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Molecules 2022, 27(9), 2742; https://doi.org/10.3390/molecules27092742
Submission received: 27 February 2022 / Revised: 20 April 2022 / Accepted: 21 April 2022 / Published: 24 April 2022
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)
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Abstract

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.
Keywords: soft tissue sarcoma; rhabdomyosarcoma; RTK/RAS/PI3K; PI3K inhibitor; synergism; drug repurposing soft tissue sarcoma; rhabdomyosarcoma; RTK/RAS/PI3K; PI3K inhibitor; synergism; drug repurposing

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MDPI and ACS Style

Piazzi, M.; Bavelloni, A.; Cenni, V.; Salucci, S.; Bartoletti Stella, A.; Tomassini, E.; Scotlandi, K.; Blalock, W.L.; Faenza, I. Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. Molecules 2022, 27, 2742. https://doi.org/10.3390/molecules27092742

AMA Style

Piazzi M, Bavelloni A, Cenni V, Salucci S, Bartoletti Stella A, Tomassini E, Scotlandi K, Blalock WL, Faenza I. Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. Molecules. 2022; 27(9):2742. https://doi.org/10.3390/molecules27092742

Chicago/Turabian Style

Piazzi, Manuela, Alberto Bavelloni, Vittoria Cenni, Sara Salucci, Anna Bartoletti Stella, Enrica Tomassini, Katia Scotlandi, William L. Blalock, and Irene Faenza. 2022. "Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells" Molecules 27, no. 9: 2742. https://doi.org/10.3390/molecules27092742

APA Style

Piazzi, M., Bavelloni, A., Cenni, V., Salucci, S., Bartoletti Stella, A., Tomassini, E., Scotlandi, K., Blalock, W. L., & Faenza, I. (2022). Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. Molecules, 27(9), 2742. https://doi.org/10.3390/molecules27092742

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