Melittin from Apis florea Venom as a Promising Therapeutic Agent for Skin Cancer Treatment

Abstract

Melittin, a major component found in bee venom, is produced by the Apis species of the honey bee. In this study, the effect of melittin derived from Apis florea (Mel-AF), which is a wild honey bee species that is indigenous to Thailand, was investigated against human malignant melanoma (A375) cells. In this study, Mel-AF exhibited considerable potential in the anti-proliferative action of A375 cells. Subsequently, the cellular mechanism of Mel-AF that induced cell death was investigated in terms of apoptosis. As a result, gene and protein expression levels, which indicated the activation of cytochrome-c release and caspase-9 expression, eventually triggered the release of the caspase-3 executioner upon Mel-AF. We then determined that apoptosis-mediated cell death was carried out through the intrinsic mitochondrial pathway. Moreover, advanced abilities, including cell motility and invasion, were significantly suppressed. Mel-AF manipulated the actin arrangement via the trapping of stress fibers that were found underneath the membrane, which resulted in the defective actin cytoskeleton organization. Consequently, the expression of EGFR, a binding protein to F-actin, was also found to be suppressed. This outcome strongly supports the effects of Mel-AF in the inhibition of progressive malignant activity through the disruption of actin cytoskeleton-EGFR interaction and the EGFR signaling system. Thus, the findings of our current study indicate the potential usefulness of Mel-AF in cancer treatments as an apoptosis inducer and a potential actin-targeting agent.

Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

“…Despite the significantly highest antineoplastic activity showed by FLV-MEL combination, the activity of MEL alone is also worth of mention. In fact, as showed in almost all in vitro cell experiments, the antineoplastic activity of MEL alone used at a sub-toxic concentration (IC10) was higher than that of the free drug (FLV-R) and is in accordance with several recent research studies ( Sangboonruang et al, 2020 ; Yu et al, 2020 ) such as that carried out by Duffy et al showing the ability of MEL to suppress epidermal growth factor receptors 1 and 2 (EGFR and HER2) activation in the aggressive triple-negative and HER2-enriched breast cancer subtypes ( Duffy et al, 2020 ). The present findings also confirm that the combination of this natural product with other antineoplastic drugs results in a more powerful anticancer activity.…”

Pharmaceutical Prospects of Bee Products: Special Focus on Anticancer, Antibacterial, Antiviral, and Antiparasitic Properties

“…One of the most notable components in bee venom is melittin, a major protein substituent found in most venoms of bee species under the Apis genus. Melittin from Apis florea and Apis mellifera have been shown to exhibit a relatively strong anticancer activity (IC 50 = 3.38 and 4.97 µg/mL, respectively) when challenged against A375 (human malignant melanoma), comparable to that of doxorubicin [124]. A cytotoxicity examination of melittin against HeLa, WiDr and Vero cell lines was also reported, showing anticancer activities with IC 50 values of 2.54, 2.68 and 3.53 µg/mL, respectively [125].…”

“…At a concentration of 0.5 µg/mL, melittin is able to reduce the viability of cultured AGS cells, a gastric cancer model [127]. The anticancer mechanism of melittin is possibly related to its ability to activate the apoptotic pathway via cytochrome-c discharge and therefore activates caspase-9 which leads to the activation of caspase-3 [124]. In relation to this, further investigation was carried out which indicated that melittin prevents the invasion and migration of melanoma cells in a metastatic cell model, mainly though interference with F-actin reorganization and epidermal growth factor receptor (EGFR) activation [124].…”

“…The anticancer mechanism of melittin is possibly related to its ability to activate the apoptotic pathway via cytochrome-c discharge and therefore activates caspase-9 which leads to the activation of caspase-3 [124]. In relation to this, further investigation was carried out which indicated that melittin prevents the invasion and migration of melanoma cells in a metastatic cell model, mainly though interference with F-actin reorganization and epidermal growth factor receptor (EGFR) activation [124]. Although it is encouraging that melittin seems to be a promising anticancer agent, there is a growing concern that this protein may also be active against normal cells.…”

Hyaluronic Acid Coating Reduces the Leakage of Melittin Encapsulated in Liposomes and Increases Targeted Delivery to Melanoma Cells

“…In conclusion, HA-modified liposomes were able to specifically deliver the drug to melanomas and strengthen therapeutic action and improved the bioavailability and stability of the preparation. Melittin has been reported to have potential against melanoma [ 38 ]. Thus, our results suggest that the new targeted drug delivery system is a promising strategy for the treatment of melanoma.…”