Reema M. Alzeer

The search for NF-κB blockers to optimize antioxidants and counteract inflammation and carcinogenesis has identified several promising natural compounds, encompassing curcumin. Nonetheless, despite the pleiotropic health attributes of curcumin and established safety, its in vivo efficacy is limited by its poor pharmacokinetic properties, primarily due to its low bioavailability because of its low free serum concentrations and short half-life. To overcome these restrictions, we investigated the efficacy of the synthetic curcumin analog PAC in breast cancer cells. Additionally, MCF-7 and MDA-MB-231 cell lines were employed to explore the anticancer effects of PAC by assessing cell viability, apoptosis, clonogenic survival, and the expression of NF-κB, p53, Bcl-2, and Bax. Our results validate that PAC effectively inhibits cell proliferation and induces apoptosis in a dose-dependent manner. PAC also significantly enhances the radiosensitivity of breast cancer cells, indicating a potential synergistic effect with radiation therapy. Mechanistically, PAC exerts anticancer effects by inhibiting NF-κB signaling and modulating apoptotic genes like p53, Bax, and Bcl-2. These findings highlight its potential as a breast cancer therapeutic, enhancing existing treatments.

Venom peptides are promising agents in the development of unconventional anticancer therapeutic agents. This study explored the potential of Pilosulin-3, a recombinant peptide from the venom of the Australian jack jumper ant “Myrmecia pilosula”, as a cytotoxic and radiosensitizing agent in MCF-7 and MDA-MB-231 breast cancer (BC) cell lines. Pilosulin-3’s cytotoxicity was evaluated across a wide range of concentrations using a proliferation assay. Cell cycle progression and apoptosis were examined at the inhibitory concentration 25% (IC25) and IC50 of Pilosulin-3, both with and without a 4Gy X-ray irradiation dose. Radiosensitivity was assessed at IC25 using the clonogenic survival assay. The study revealed that Pilosulin-3 exerted a concentration-dependent cytotoxic effect, with IC25 and IC50 values of 0.01 and 0.5 µM, respectively. In silico screening indicated high selectivity of Pilosulin-3 peptide, which was predicted to be the most likely anticancer agent (PROB = 0.997) with low hemolytic activity (PROP = 0.176). Although Pilosulin-3 exhibited a significant (p < 0.05) G2/M cell cycle arrest in combination with radiation, there was no discernible effect on apoptosis induction or cell survival following irradiation. In conclusion, Pilosulin-3 proved to be cytotoxic to BC cells and induced a cytostatic effect (G2/M arrest) when combined with radiation. However, it did not enhance the efficacy of cell killing by irradiation. While it holds potential as a cytotoxic agent in breast cancer treatment, its application as a radiosensitizer does not find support in these results.