A Comparative Study of Melittins from Apis florea and Apis mellifera as Cytotoxic Agents Against Non-Small Cell Lung Cancer (NSCLC) Cells and Their Combination with Gefitinib

Lung cancer remains one of the most lethal malignancies, often diagnosed at advanced stages, leading to limited treatment options. Thus, identifying natural products with potent anti-cancer activity is crucial for improving treatment outcomes. While the melittin from <i>Apis mellifera</i> (Mel-AM) has been extensively studied, the melittin from <i>Apis florea</i> (Mel-AF), a bee species native to Southeast Asia, remains relatively underexplored. These peptides were comparatively investigated against non-small cell lung cancer (NSCLC) cell lines, A549, NCI-H460, and NCI-H1975. Mel-AF demonstrated a superior cytotoxicity (cytotoxic concentration 50% (CC50) = 2.55-5.06 µg/mL) compared to Mel-AM (CC50 = 4.32-8.48 µg/mL). While both peptides induced apoptosis via the intrinsic mitochondrial pathway, Mel-AF exhibited a more pronounced effect, significantly enhancing apoptosis induction compared to Mel-AM. Both peptides inhibited cell migration and invasion; however, when combined with gefitinib, Mel-AF more effectively enhanced the drug's inhibitory effects on the A549 and NCI-H460 cell lines compared to Mel-AM, underscoring its superior potential as a therapeutic agent. Altogether, we demonstrated that these peptides induced apoptosis in NSCLC cell lines, with Mel-AF having more pronounced effects, and the combination use of peptides with a chemotherapeutic drug showed synergistic effects against lung cancer cells, enhancing their practical use in lung cancer treatments.