| Summary: | Over recent decades, much attention has been given to imply the natural products in cancer therapy alone or in combination with other established procedures. Insects have a rich history in traditional medicine across the globe, which holds promise for the future of natural product drug discovery. Cecropins, peptides produced by insects, are components of a defense system against infections and are well known to exert antimicrobial and antitumor capabilities. The present study aimed to investigate, for the first time, the role of curcumin in enhancing the anticancer effect of <i>Musca domestica</i> larval hemolymph. Third larval instars of <i>M. domestica</i> were injected with curcumin and the hemolymph was picked at 4, 8, and 24 h post-curcumin injection. <i>M. domestica</i> cecropin A (<i>Md</i>CecA) was evaluated in control and injected larval hemolymphs. The cytotoxicity on breast cancer cell lines (MCF-7) and normal Vero cells was assessed to be comparable to control larval hemolymph. Curcumin-injected larval hemolymphs exhibited significant cytotoxicity with respect to the uninjected ones against MCF-7; however, Vero cells showed no cytotoxicity. The IC<sub>50</sub> was 106 ± 2.9 and 388 ± 9.2 μg/mL for the hemolymphs of injected larvae at 4 and 8 h, respectively, while the control larval hemolymph revealed the IC<sub>50</sub> of >500 μg/mL. For mechanistic anticancer evaluation, concentrations of 30, 60, and 100 μg/mL of curcumin-injected larval hemolymphs were examined. A significant G<sub>2</sub>/M cell cycle arrest was observed, confirming the anti-proliferative properties of hemolymphs over the tested concentrations. The <i>Md</i>CecA transcripts were significantly (<i>p</i> < 0.05) upregulated at 4 and 8 h post-injection, while a significant downregulation was observed after 24 h. Cecropin quantification by LC–MS revealed that <i>Md</i>CecA peptides have the highest expression in the hemolymph of the treated larvae at 8 h relative to the control group. The upregulation of cecropin expression at mRNA and protein levels may be attributed to the curcumin stimulation and linked to the increased cytotoxicity toward the cancer cell line. In conclusion, the results suggest that the apoptotic and anti-proliferative effects of <i>M. domestica</i> hemolymph on MCF-7 cells following the curcumin injection can be used as a natural candidate in future pharmaceutical industries.
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