{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:26:30Z","timestamp":1785770790559,"version":"3.56.0"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia driven by the PML\/RAR\u03b1 fusion protein. Standard treatment with all-trans retinoic acid (ATRA) combined with chemotherapy is effective, but resistance and adverse effects remain significant challenges. Melittin, the primary peptide component of bee venom, has demonstrated potent anticancer activity across multiple leukemia subtypes through mitochondrial-dependent mechanisms. Building upon this established evidence, we investigated melittin\u2019s therapeutic potential in APL to address the specific clinical challenge of ATRA resistance. Methods: The cytotoxic and pro-apoptotic effects of melittin were studied on the human APL cell line HL-60. Cell viability was assessed using MTT and trypan blue assays. Mitochondrial membrane potential (MMP) was measured with JC-1 staining. Apoptosis was quantified using Annexin V\/propidium iodide flow cytometry, caspase-3\/7 activity assays, and real-time PCR analysis of apoptosis-related genes (BCL-2, BAX, APAF-1, CASP-3, CASP-8, CASP-9). Results: Melittin reduced HL-60 cell viability in a dose- and time-dependent manner, with significant decreases after 24 and 48 h. MMP analysis revealed mitochondrial depolarization, and Annexin V staining confirmed the induction of apoptosis. Caspase-3\/7 activity increased markedly, supporting activation of the intrinsic apoptotic pathway. Gene expression profiling revealed downregulation of the anti-apoptotic BCL-2 and upregulation of the pro-apoptotic BAX, APAF1, and CASP3. At the same time, CASP8 and CASP9 showed no significant changes, suggesting a predominant involvement of the intrinsic pathway. Conclusions: These findings confirm and extend established evidence by demonstrating that melittin\u2019s mitochondrial apoptotic mechanism is consistently active in promyelocytic HL-60 model (PML\/RAR\u03b1-negative). This retinoid-independent mechanism suggests potential therapeutic utility for ATRA-resistant cases or as a complementary strategy in APL treatment. However, selectivity validation in non-cancerous hematopoietic cells represents an important future research priority.<\/jats:p>","DOI":"10.3390\/molecules30204093","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:57:42Z","timestamp":1760529462000},"page":"4093","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pro-Apoptotic and Cytotoxic Effects of Melittin on HL-60 Acute Promyelocytic Leukemia Cells: Implications for Retinoid-Independent Therapy"],"prefix":"10.3390","volume":"30","author":[{"given":"Maksymilian","family":"Stela","sequence":"first","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Ceremuga","sequence":"additional","affiliation":[{"name":"Military Institute of Armoured and Automotive Technology, Okuniewska 1, 05-070 Sulej\u00f3wek, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-2451","authenticated-orcid":false,"given":"Natalia","family":"Cichon","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-7339","authenticated-orcid":false,"given":"Tomasz","family":"Poplawski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Pharmaceutical Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7566-4205","authenticated-orcid":false,"given":"Marcin","family":"Podogrocki","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9873-9521","authenticated-orcid":false,"given":"Leslaw","family":"Gorniak","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-4097","authenticated-orcid":false,"given":"Micha\u0142","family":"Bijak","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.0954-6820.1957.tb00124.x","article-title":"Acute promyelocytic leukemia","volume":"159","author":"Hillestad","year":"1957","journal-title":"Acta. 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