The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells
Author
Simioni, Carolina; Cani, Alice; Martelli, Alberto M.; Zauli, Giorgio; Alameen, Ayman A.M.; Ultimo, Simona; Tabellini, Giovanna; McCubrey, James A.; Capitani, Silvano; Neri, Luca M.
Abstract
Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis.
In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration.
In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1α and of VEGF.
Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy
Date
2015-07
Citation:
APA:
Simioni, Carolina, & Cani, Alice, & Martelli, Alberto M., & Zauli, Giorgio, & Alameen, Ayman A.M., & Ultimo, Simona, & Tabellini, Giovanna, & McCubrey, James A., & Capitani, Silvano, & Neri, Luca M.. (July 2015).
The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells.
Oncotarget,
6(19),
17147-
17160. Retrieved from
http://hdl.handle.net/10342/5555
MLA:
Simioni, Carolina, and Cani, Alice, and Martelli, Alberto M., and Zauli, Giorgio, and Alameen, Ayman A.M., and Ultimo, Simona, and Tabellini, Giovanna, and McCubrey, James A., and Capitani, Silvano, and Neri, Luca M..
"The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells". Oncotarget.
6:19. (17147-17160),
July 2015.
June 29, 2024.
http://hdl.handle.net/10342/5555.
Chicago:
Simioni, Carolina and Cani, Alice and Martelli, Alberto M. and Zauli, Giorgio and Alameen, Ayman A.M. and Ultimo, Simona and Tabellini, Giovanna and McCubrey, James A. and Capitani, Silvano and Neri, Luca M.,
"The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells," Oncotarget 6, no.
19 (July 2015),
http://hdl.handle.net/10342/5555 (accessed
June 29, 2024).
AMA:
Simioni, Carolina, Cani, Alice, Martelli, Alberto M., Zauli, Giorgio, Alameen, Ayman A.M., Ultimo, Simona, Tabellini, Giovanna, McCubrey, James A., Capitani, Silvano, Neri, Luca M..
The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. Oncotarget.
July 2015;
6(19):
17147-17160.
http://hdl.handle.net/10342/5555. Accessed
June 29, 2024.
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