Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines
Abstract Background: Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. Rhopalurus junceus venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells in vitro and suggested that NSCLC was the subtype most susceptible t...
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2025-02-01
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| Series: | Journal of Venomous Animals and Toxins including Tropical Diseases |
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| author | Alexis Díaz-García Ángel Garrido Jenny Laura Ruiz-Fuentes Tamara Hermosilla Diego Varela |
| author_facet | Alexis Díaz-García Ángel Garrido Jenny Laura Ruiz-Fuentes Tamara Hermosilla Diego Varela |
| author_sort | Alexis Díaz-García |
| collection | DOAJ |
| description | Abstract Background: Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. Rhopalurus junceus venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells in vitro and suggested that NSCLC was the subtype most susceptible to the treatment. Methods: This study evaluated the effect of Rhopalurus junceus scorpion venom on cell viability, in non-cancerous (MRC-5, lung; CHO-K1, ovary) and NSCLC (A549; NCI-H460) cell lines. The effects on cell cycle, apoptosis, and cell signaling-related proteins were determined by flow cytometry and WB. Protein fractions responsible for the observed effect were identified using HPLC. Results: Scorpion venom was more effective against NSCLC than non-cancerous cells. Emax values were 20.0 ± 5.8% and 22.47 ± 6.02% in A549 and NCI-H460 cancer cells, respectively, as compared to 50 ± 8.1% in MRC-5 and 54.99 ± 7.39% in CHO-K1 cells. It arrested NSCLC cells in the G2/M phase, while non-cancerous cells were arrested in the S (MRC-5) or G0/G1 (CHO-K1) phases. No changes were observed in the Bax/Bcl-2 or the cleaved-caspase 3/Total caspase 3 ratios in cells treated with venom. Likewise, the scorpion venom treatment did not affect p-ERK, p-AKT, or p-38MAPK protein levels. In contrast, scorpion venom treatment increased the cytosolic apoptosis-inducing factor (AIF) in A549 cells, indicating caspase-independent apoptosis. Additionally, combined etoposide/venom exposure provoked G2/M arrest and apoptosis in NSCLC more strongly than either substance alone. Furthermore, upon crude venom fractioning through RP-HPLC, we found two soluble fractions with high cytotoxic effects. Conclusion: The present study concludes that a specific fraction of Rhopalurus junceus venom reduces cell viability of NSCLC cells. The AIF protein plays a key role in mediating caspase-independent apoptotic cell death. These findings suggest that Rhopalurus junceus venom enhances the anticancer effect of etoposide in vitro by causing cell cycle arrest and caspase-independent apoptosis. |
| format | Article |
| id | doaj-art-1a37d78f23b04f3da2931af6d95c6cb1 |
| institution | Kabale University |
| issn | 1678-9199 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | SciELO |
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| series | Journal of Venomous Animals and Toxins including Tropical Diseases |
| spelling | doaj-art-1a37d78f23b04f3da2931af6d95c6cb12025-02-04T07:42:19ZengSciELOJournal of Venomous Animals and Toxins including Tropical Diseases1678-91992025-02-013110.1590/1678-9199-jvatitd-2024-0035Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell linesAlexis Díaz-Garcíahttps://orcid.org/0000-0002-7784-7846Ángel GarridoJenny Laura Ruiz-Fuenteshttps://orcid.org/0000-0002-2509-4328Tamara HermosillaDiego Varelahttps://orcid.org/0000-0002-9352-414XAbstract Background: Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. Rhopalurus junceus venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells in vitro and suggested that NSCLC was the subtype most susceptible to the treatment. Methods: This study evaluated the effect of Rhopalurus junceus scorpion venom on cell viability, in non-cancerous (MRC-5, lung; CHO-K1, ovary) and NSCLC (A549; NCI-H460) cell lines. The effects on cell cycle, apoptosis, and cell signaling-related proteins were determined by flow cytometry and WB. Protein fractions responsible for the observed effect were identified using HPLC. Results: Scorpion venom was more effective against NSCLC than non-cancerous cells. Emax values were 20.0 ± 5.8% and 22.47 ± 6.02% in A549 and NCI-H460 cancer cells, respectively, as compared to 50 ± 8.1% in MRC-5 and 54.99 ± 7.39% in CHO-K1 cells. It arrested NSCLC cells in the G2/M phase, while non-cancerous cells were arrested in the S (MRC-5) or G0/G1 (CHO-K1) phases. No changes were observed in the Bax/Bcl-2 or the cleaved-caspase 3/Total caspase 3 ratios in cells treated with venom. Likewise, the scorpion venom treatment did not affect p-ERK, p-AKT, or p-38MAPK protein levels. In contrast, scorpion venom treatment increased the cytosolic apoptosis-inducing factor (AIF) in A549 cells, indicating caspase-independent apoptosis. Additionally, combined etoposide/venom exposure provoked G2/M arrest and apoptosis in NSCLC more strongly than either substance alone. Furthermore, upon crude venom fractioning through RP-HPLC, we found two soluble fractions with high cytotoxic effects. Conclusion: The present study concludes that a specific fraction of Rhopalurus junceus venom reduces cell viability of NSCLC cells. The AIF protein plays a key role in mediating caspase-independent apoptotic cell death. These findings suggest that Rhopalurus junceus venom enhances the anticancer effect of etoposide in vitro by causing cell cycle arrest and caspase-independent apoptosis.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992025000100302&lng=en&tlng=enApoptosisCell cycle arrestRhopalurus junceusScorpion venomSynergism |
| spellingShingle | Alexis Díaz-García Ángel Garrido Jenny Laura Ruiz-Fuentes Tamara Hermosilla Diego Varela Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines Journal of Venomous Animals and Toxins including Tropical Diseases Apoptosis Cell cycle arrest Rhopalurus junceus Scorpion venom Synergism |
| title | Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines |
| title_full | Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines |
| title_fullStr | Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines |
| title_full_unstemmed | Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines |
| title_short | Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines |
| title_sort | rhopalurus junceus scorpion venom induces g2 m cell cycle arrest and apoptotic cell death in human non small lung cancer cell lines |
| topic | Apoptosis Cell cycle arrest Rhopalurus junceus Scorpion venom Synergism |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992025000100302&lng=en&tlng=en |
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