A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

Abstract

Thymosin alpha 1 (Tα1) is commonly used for treating several diseases; however its usage has been limited because of poor penetration of the target tissue, such as tumor cells. In the present study, Tα1-iRGD, a peptide by conjugating Tα1 with the iRGD fragment, was evaluated its performance in MCF-7 and MDA-MB-231 human breast cancer cells. Compared with the wild-type peptide, Tα1-iRGD was more selective in binding tumor cells in the cell attachment assay. Furthermore, the MTT assay confirmed that Tα1-iRGD proved more effective in significantly inhibiting the growth of MCF-7 cells in contrast to the general inhibition displayed by Tα1. Further, conjugation of Tα1 with iRGD preserved the immunomodulatory activity of the drug by increasing the proliferation of mouse spleen lymphocytes. Further, compared with Tα1 treatment, Tα1-iRGD treatment of MCF-7 cells considerably increased the number of cells undergoing apoptosis, resulting in a dose-dependent inhibition of cancer cell growth, which was associated with a much better effect on up-regulation of the expression of BCL2-associated X protein (Bax), caspase 9, etc. More importantly, treatment with Ta1-iRGD was more efficacious than treatment with Ta1 in vivo. This study highlights the importance of iRGD on enhancement of cell penetration and tumor accumulation. In summary, our findings demonstrate that the novel modified Tα1 developed in this study has the potential to be used for treating breast cancer.

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

“…At the same time, the number of apoptotic cells increased by 22-fold ( Figure 4B). These results are in agreement with the findings of other authors (46,47).…”

“…We then evaluated the effect of chronic treatment with Tα-1 on the proliferation and apoptosis of MCF-7 breast cancer cells. Indeed, various research groups reported that long-term treatment (72 hours) with Tα-1 (in the 150-500 μM concentration range) decreases the proliferation rate of MCF-7 and causes cell apoptosis (46,47). Therefore, we plated MCF-7 at low density on 96-well plates suitable for confocal high-content imaging and evaluated cell proliferation for 72 hours following treatment with Tα-1 (100 ng/ml) or scrambled peptide (100 ng/ml).…”

Thymosin alpha‐1; a natural peptide inhibits cellular proliferation, cell migration, the level of reactive oxygen species and promotes the activity of antioxidant enzymes in human lung epithelial adenocarcinoma cell line (A549)

“…In contrary to our findings, Guo et al indicated that in breast cancer cells, PTEN mediates Thα1‐induced apoptosis by mitochondrial death cascade and suppression of the PI3K/Akt/mTOR signaling pathway . Furthermore, another research suggested that exposure of MCF‐7 cells to Thα1‐iRGD enhanced the apoptotic cells through upregulation of the expression of Bax and caspase 9, which causes to suppress the growth of cancer cells . Fan et al found that after treatment HL‐60, K562, and K562/ADM with Thα1, the features of apoptosis including nuclei condensation and cell morphology appeared …”

“…Thα1 is known as an effective therapeutic peptide for the treatment of some diseases . The major actions of this peptide are activation of cytokines, chemokines, and possessing antifungal as well as antibacterial effects .…”

Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

“…Utilizing a different chemotherapeutic, Zhang et al reported that in an A549 xenograft model of non-small cell lung cancer, co-administration of iRGD along with gemcitabine lead to increased penetrance of drug to the tumor and decreased tumor volume over the treatment period of 30 days (Zhang et al, 2015). Finally, Lao et al reported that a thymosin alpha 1-iRGD conjugated form increased apoptosis of MCF-7 cells and decreased tumor volume over an 11 day treatment period when compared to thymosin alpha 1 alone (Lao et al, 2015). …”