Paclitaxel (PTX) is a chemotherapeutic agent affecting microtubule polymerization. The efficacy of PTX depends on the type of tumor, and its improvement would be beneficial in patients' treatment. Therefore, we tested the effect of slow sulfide donor GYY4137 on paclitaxel sensitivity in two different breast cancer cell lines, MDA-MB-231, derived from a triple negative cell line, and JIMT1, which overexpresses HER2 and is resistant to trastuzumab. In JIMT1 and MDA-MB-231 cells, we compared IC50 and some metabolic (apoptosis induction, lactate/pyruvate conversion, production of reactive oxygen species, etc.), morphologic (changes in cytoskeleton), and functional (migration, angiogenesis) parameters for PTX and PTX/GYY4137, aiming to determine the mechanism of the sensitization of PTX. We observed improved sensitivity to paclitaxel in the presence of GYY4137 in both cell lines, but also some differences in apoptosis induction and pyruvate/lactate conversion between these cells. In MDA-MB-231 cells, GYY4137 increased apoptosis without affecting the IP3R1 protein, changing the morphology of the cytoskeleton. A mechanism of PTX sensitization by GYY4137 in JIMT1 cells is distinct from MDA-MB-231, and remains to be further elucidated. We suggest different mechanisms of action for H2S on the paclitaxel treatment of MDA-MB-231 and JIMT1 breast cancer cell lines.

Department of Physiology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Institute of Clinical and Translational Research Biomedical Research Center Slovak Academy of Sciences Dubravska Cesta 9 845 05 Bratislava Slovakia

Institute of Virology Biomedical Research Center Slovak Academy of Sciences Dubravska Cesta 9 84505 Bratislava Slovakia

Zobrazit více v PubMed

Dewi C., Fristiohady A., Amalia R., Khairul Ikram N.K., Ibrahim S., Muchtaridi M. Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line. Molecules. 2022;27:3661. doi: 10.3390/molecules27123661. PubMed DOI PMC

Chiu H.W., Lin H.Y., Tseng I.J., Lin Y.F. OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer. Oncotarget. 2018;9:553–565. doi: 10.18632/oncotarget.23074. PubMed DOI PMC

Rugo H.S., Umanzor G.A., Barrios F.J., Vasallo R.H., Chivalan M.A., Bejarano S., Ramírez J.R., Fein L., Kowalyszyn R.D., Kramer E.D., et al. Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. J. Clin. Oncol. 2023;41:65–74. doi: 10.1200/JCO.21.02953. PubMed DOI PMC

Gao D., Asghar S., Ye J., Zhang M., Hu R., Wang Y., Huang L., Yuan C., Chen Z., Xiao Y. Dual-targeted enzyme-sensitive hyaluronic acid nanogels loading paclitaxel for the therapy of breast cancer. Carbohydr. Polym. 2022;294:119785. doi: 10.1016/j.carbpol.2022.119785. PubMed DOI

Attia Y.M., El-Kersh D.M., Ammar R.A., Adel A., Khalil A., Walid H., Eskander K., Hamdy M., Reda N., Mohsen N.E., et al. Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer. Chem. Biol. Interact. 2020;315:10886. doi: 10.1016/j.cbi.2019.108865. PubMed DOI

Mohammadhosseinpour S., Weaver A., Sudhakaran M., Ho L.-C., Le T., Doseff A.I., Medina-Bolivar F. Arachidin-1, a Prenylated Stilbenoid from Peanut, Enhances the Anticancer Effects of Paclitaxel in Triple-Negative Breast Cancer Cells. Cancers. 2023;15:399. doi: 10.3390/cancers15020399. PubMed DOI PMC

Abu Samaan T.M., Samec M., Liskova A., Kubatka P., Büsselberg D. Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer. Biomolecules. 2019;9:789. doi: 10.3390/biom9120789. PubMed DOI PMC

Yang Y.H., Mao J.W., Tan X.L. Research progress on the source, production, and anti-cancer mechanisms of paclitaxel. Chin. J. Nat. Med. 2020;18:890–897. doi: 10.1016/S1875-5364(20)60032-2. PubMed DOI

Kajsik M., Chovancova B., Liskova V., Babula P., Krizanova O. Slow sulfide donor GYY4137 potentiates effect of paclitaxel on colorectal carcinoma cells. Eur. J. Pharmacol. 2022;922:174875. doi: 10.1016/j.ejphar.2022.174875. PubMed DOI

Mathai J.C., Missner A., Kügler P., Saparov S.M., Zeidel M.L., Lee J.K., Pohl P. No facilitator required for membrane transport of hydrogen sulfide. Proc. Natl. Acad. Sci. USA. 2009;106:16633–16638. doi: 10.1073/pnas.0902952106. PubMed DOI PMC

Nagy P., Palinkas Z., Nagy A., Budai B., Toth I., Vasas A. Chemical aspects of hydrogen sulfide measurements in physiological samples. Biochim. Biophys. Acta. 2014;1840:876–891. doi: 10.1016/j.bbagen.2013.05.037. PubMed DOI

Vitvitsky V., Kabil O., Banerjee R. High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid. Redox Signal. 2012;17:22–31. doi: 10.1089/ars.2011.4310. PubMed DOI PMC

Reis A.K.C.A., Stern A., Monteiro H.P. S-nitrosothiols and H2S donors: Potential chemo-therapeutic agents in cancer. Redox Biol. 2019;27:101190. doi: 10.1016/j.redox.2019.101190. PubMed DOI PMC

Wu D., Hu Q., Zhu Y. Therapeutic application of hydrogen sulfide donors: The potential and challenges. Front. Med. 2016;10:18–27. doi: 10.1007/s11684-015-0427-6. PubMed DOI

Wu D., Li J., Zhang Q., Tian W., Zhong P., Liu Z., Wang H., Wang H., Ji A., Li Y. Exogenous Hydrogen Sulfide Regulates the Growth of Human Thyroid Carcinoma Cells. Oxidative Med. Cell. Longev. 2019;2019:6927298. doi: 10.1155/2019/6927298. PubMed DOI PMC

Nadkarni D.V. Conjugations to Endogenous Cysteine Residues. Methods Mol. Biol. 2020;2078:37–49. PubMed

Yang D., Wei X., Zhang Z., Chen X., Zhu R., Oh Y., Gu N. Tris (2-chloroethyl) phosphate (TCEP) induces obesity and hepatic steatosis via FXR-mediated lipid accumulation in mice: Long-term exposure as a potential risk for metabolic diseases. Chem. Biol. Interact. 2022;363:110027. doi: 10.1016/j.cbi.2022.110027. PubMed DOI

Valabrega G., Capellero S., Cavalloni G., Zaccarello G., Petrelli A., Migliardi G., Milani A., Peraldo-Neia C., Gammaitoni L., Sapino A., et al. HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Res. Treat. 2011;130:29–40. doi: 10.1007/s10549-010-1281-5. PubMed DOI

Rezuchova I., Hudecova S., Soltysova A., Matuskova M., Durinikova E., Chovancova B., Zuzcak M., Cihova M., Burikova M., Penesova A., et al. Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells. Cell Death Dis. 2019;10:186. doi: 10.1038/s41419-019-1433-4. PubMed DOI PMC

Ta N., Li C., Fang Y., Liu H., Lin B., Jin H., Tian L., Zhang H., Zhang W., Xi Z. Toxicity of TDCPP and TCEP on PC12 cell: Changes in CAMKII, GAP43, tubulin and NF-H gene and protein levels. Toxicol. Lett. 2014;227:164–171. doi: 10.1016/j.toxlet.2014.03.023. PubMed DOI

Pastorek M., Simko V., Takacova M., Barathova M., Bartosova M., Hunakova L., Sedlakova O., Hudecova S., Krizanova O., Dequiedt F., et al. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy. Int. J. Oncol. 2015;47:51–60. doi: 10.3892/ijo.2015.2987. PubMed DOI PMC

Chovancova B., Liskova V., Miklikova S., Hudecova S., Babula P., Penesova A., Sevcikova A., Durinikova E., Novakova M., Matuskova M., et al. Calcium signaling affects migration and proliferation differently in individual cancer cells due to nifedipine treatment. Biochem. Pharmacol. 2020;171:113695. doi: 10.1016/j.bcp.2019.113695. PubMed DOI

Lau D.H., Xue L., Young L.J., Burke P.A., Cheung A.T. Paclitaxel (Taxol): An inhibitor of angiogenesis in a highly vascularized transgenic breast cancer. Cancer Biother. Radiopharm. 1999;14:31 – 36.. doi: 10.1089/cbr.1999.14.31. PubMed DOI

Hunter C.P. Epidemiology, stage at diagnosis, and tumor biology of breast carcinoma in multiracial and multiethnic populations. Cancer. 2000;88:1193–1202. doi: 10.1002/(SICI)1097-0142(20000301)88:5+<1193::AID-CNCR3>3.0.CO;2-D. PubMed DOI

Sakach E., O’Regan R., Meisel J., Li X. Molecular classification of triple negative breast cancer and the emergence of targeted therapies. Clin. Breast Cancer. 2021;21:509–520. doi: 10.1016/j.clbc.2021.09.003. PubMed DOI

Zhao S., Zuo W.-J., Shao Z.-M., Jiang Y.-Z. Molecular subtypes and precision treatment of triple-negative breast cancer. Ann. Transl. Med. 2020;8:499. doi: 10.21037/atm.2020.03.194. PubMed DOI PMC

Dong Q., Yang B., Han J.-G., Zhang M.-M., Liu W., Zhang X., Yu H.-L., Liu Z.-G., Zhang S.-H., Li T., et al. A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways. Cancer Lett. 2019;455:60–72. doi: 10.1016/j.canlet.2019.04.031. PubMed DOI

Nakayama S., Torikoshi Y., Takahashi T., Yoshida T., Sudo T., Matsushima T., Kawasaki Y., Katayama A., Gohda K., Hortobagyi G.N., et al. Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells. Breast Cancer Res. 2009;11:R12. doi: 10.1186/bcr2231. PubMed DOI PMC

Jeansonne D.P., Koh G.Y., Zhang F., Kirk-Ballard H., Wolff L., Liu D., Eilertsen K., Liu Z. Paclitaxel-induced apoptosis is blocked by camptothecin in human breast and pancreatic cancer cells. Oncol. Rep. 2011;25:1473–1480. PubMed

Haghnavaz N., Asghari F., Elieh Ali Komi D., Shanehbandi D., Baradaran B., Kazemi T. HER2 positivity may confer resistance to therapy with paclitaxel in breast cancer cell lines. Artif. Cells Nanomed. Biotechnol. 2018;46:518–523. doi: 10.1080/21691401.2017.1326927. PubMed DOI

Markova J., Hudecova S., Soltysova A., Sirova M., Csaderova L., Lencesova L., Ondrias K., Krizanova O. Sodium/calcium exchanger is upregulated by sulfide signaling, forms complex with the β1 and β3 but not β2 adrenergic receptors, and induces apoptosis. Pflügers Arch. Eur. J. Physiol. 2014;466:1329–1342. doi: 10.1007/s00424-013-1366-1. PubMed DOI

Bae J., Kumazoe M., Yamashita S., Tachibana H. Hydrogen sulphide donors selectively potentiate a green tea polyphenol EGCG-induced apoptosis of multiple myeloma cells. Sci. Rep. 2017;7:6665. doi: 10.1038/s41598-017-06879-5. PubMed DOI PMC

Tian Y., Ge Z., Xu M., Ge X., Zhao M., Ding F., Yin J., Wang X., You Y., Shi Z., et al. Diallyl trisulfide sensitizes radiation therapy on glioblastoma through directly targeting thioredoxin 1. Free. Radic. Biol. Med. 2022;189:157–168. doi: 10.1016/j.freeradbiomed.2022.07.019. PubMed DOI

Henklewska M., Pawlak A., Pruchnik H., Obminska-Mrukowicz B. Complex of Platinum(II) with Tris(2-carboxyethyl)phosphine Induces Apoptosis in Canine Lymphoma/Leukemia Cell Lines. Anticancer Res. 2017;37:539–546. doi: 10.21873/anticanres.11346. PubMed DOI

Perillo B., Di Donato M., Pezone A., Di Zazzo E., Giovannelli P., Galasso G., Castoria G., Migliaccio A. ROS in cancer therapy: The bright side of the moon. Exp. Mol. Med. 2020;52:192–203. doi: 10.1038/s12276-020-0384-2. PubMed DOI PMC

Lencesova L., Hudecova S., Csaderova L., Markova J., Soltysova A., Pastorek M., Sedlak J., Wood M.E., Whiteman M., Ondrias K., et al. Sulphide signalling potentiates apoptosis through the up-regulation of IP3 receptor types 1 and 2. Acta Physiol. 2013;208:350–361. doi: 10.1111/apha.12105. PubMed DOI

Pal S., Sharma A., Mathew S.P., Jaganathan B.G. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics. Front. Immunol. 2022;13:955476. doi: 10.3389/fimmu.2022.955476. PubMed DOI PMC

Zhou S., Liu J., Wan A., Zhang Y., Qi X. Epigenetic regulation of diverse cell death modalities in cancer: A focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis. J. Hematol. Oncol. 2024;17:22. doi: 10.1186/s13045-024-01545-6. PubMed DOI PMC

Schell J.C., Olson K.A., Jiang L., Hawkins A.J., Van Vranken J.G., Xie J., Egnatchik R.A., Earl E.G., DeBerardinis R.J., Rutter J. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell. 2014;56:400–413. doi: 10.1016/j.molcel.2014.09.026. PubMed DOI PMC

Untereiner A.A., Olah G., Modis K., Hellmich M.R., Szabo C. H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates cellular bioenergetics in HCT116 colon cancer cells. Biochem. Pharmacol. 2017;136:86–98. doi: 10.1016/j.bcp.2017.03.025. PubMed DOI PMC

Görlach A., Bertram K., Hudecova S., Krizanova O. Calcium and ROS: A mutual interplay. Redox Biol. 2015;6:260–271. doi: 10.1016/j.redox.2015.08.010. PubMed DOI PMC

Zhang Y., Tang Y., Tang X., Wang Y., Zhang Z., Yang H. Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression. Molecules. 2022;27:7183. doi: 10.3390/molecules27217183. PubMed DOI PMC

Wedmann R., Bertlein S., Macinkovic I., Böltz S., Miljkovic J.L., Muñoz L.E., Herrmann M., Filipovic M.R. Working with "H2S": Facts and apparent artifacts. Nitric Oxide. 2014;41:85–96. doi: 10.1016/j.niox.2014.06.003. PubMed DOI

Xie Z.Z., Liu Y., Bian J.S. Hydrogen Sulfide and Cellular Redox Homeostasis. Oxidative Med. Cell. Longev. 2016;2016:6043038. doi: 10.1155/2016/6043038. PubMed DOI PMC

Hu J., Xu Z., Liao D., Jiang Y., Pu H., Wu Z., Xu X., Zhao Z., Liu J., Lu X., et al. An H2 S-BMP6 Dual-Loading System with Regulating Yap/Taz and Jun Pathway for Synergistic Critical Limb Ischemia Salvaging Therapy. Adv. Healthc. Mater. 2023;2:e2301316. doi: 10.1002/adhm.202301316. PubMed DOI

Murphy B., Bhattacharya R., Mukherjee P. Hydrogen sulfide signaling in mitochondria and disease. FASEB J. 2019;33:13098–13125. doi: 10.1096/fj.201901304R. PubMed DOI PMC

Chang Y.C., Fong Y., Tsai E.-M., Chang Y.-G., Chou H.L., Wu C.-Y., Teng Y.-N., Liu T.-C., Yuan S.-S., Chiu C.-C. Exogenous C8-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells. Int. J. Mol. Sci. 2018;19:3010. doi: 10.3390/ijms19103010. PubMed DOI PMC

de Souza Grinevicius V.M.A., Kviecinski M.R., Santos Mota N.S.R., Ourique F., Porfirio Will Castro L.S.E., Andreguetti R.R., Gomes Correia J.F., Filho D.W., Pich C.T., Pedrosa R.C. Piper nigrum ethanolic extract rich in piperamides causes ROS overproduction, oxidative damage in DNA leading to cell cycle arrest and apoptosis in cancer cells. J. Ethnopharmacol. 2016;189:139–147. doi: 10.1016/j.jep.2016.05.020. PubMed DOI

Yang C.H., Horwitz S.B. Taxol®: The First Microtubule Stabilizing Agent. Int. J. Mol. Sci. 2017;18:1733. doi: 10.3390/ijms18081733. PubMed DOI PMC

Li J., Chen S., Wang X., Shi C., Liu H., Yang J., Shi W., Guo J., Jia H. Hydrogen Sulfide Disturbs Actin Polymerization via S-Sulfhydration Resulting in Stunted Root Hair Growth. Plant Physiol. 2018;178:936–949. doi: 10.1104/pp.18.00838. PubMed DOI PMC

Mustafa A.K., Gadalla M.M., Sen N., Kim S., Mu W., Gazi S.K., Barrow R.K., Yang G., Wang R., Snyder S.H. H2S signals through protein S-sulfhydration. Sci. Signal. 2009;2:ra72. doi: 10.1126/scisignal.2000464. PubMed DOI PMC

Madurga A., Mižíková I., Ruiz-Camp J., Vadász I., Herold S., Mayer K., Fehrenbach H., Seeger W., Morty R.E. Systemic hydrogen sulfide administration partially restores normal alveolarization in an experimental animal model of bronchopulmonary dysplasia. Am. J. Physiol. Lung Cell. Mol. Physiol. 2014;306:L684–L697. doi: 10.1152/ajplung.00361.2013. PubMed DOI

Zheng D., Dong S., Li T., Yang F., Yu X., Wu J., Zhong X., Zhao Y., Wang L., Xu C., et al. Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models. Cell Physiol. Biochem. 2015;36:917–929. doi: 10.1159/000430266. PubMed DOI

Zhang Y., Chen S., Zhu J., Guo S., Yue T., Xu H., Hu J., Huang Z., Chen Z., Wang P., et al. Overexpression of CBS/H2S inhibits proliferation and metastasis of colon cancer cells through downregulation of CD44. Cancer Cell Int. 2022;22:85. doi: 10.1186/s12935-022-02512-2. PubMed DOI PMC

Jang H., Oh M., Kim Y., Choi I., Yang H.S., Ryu W., Lee S., Yoon B. Hydrogen sulfide treatment induces angiogenesis after cerebral ischemia. J. Neurosci. Res. 2014;92:1520–1528. doi: 10.1002/jnr.23427. PubMed DOI

Polhemus D.J., Kondo K., Bhushan S., Bir S.C., Kevil C.G., Murohara T., Lefer D.J., Calvert J.W. Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ. Heart Fail. 2013;6:1077–1086. doi: 10.1161/CIRCHEARTFAILURE.113.000299. PubMed DOI PMC

Papapetropoulos A., Pyriochou A., Altaany Z., Yang G., Marazioti A., Zhou Z., Jeschke M.G., Branski L.K., Herndon D.N., Wang R., et al. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc. Natl. Acad. Sci. USA. 2009;106:21972–21977. doi: 10.1073/pnas.0908047106. PubMed DOI PMC

Macabrey D., Joniová J., Gasser Q., Bechelli C., Longchamp A., Urfer S., Lambelet M., Fu C.-Y., Schwarz G., Wagnières G., et al. Sodium thiosulfate, a source of hydrogen sulfide, stimulates endothelial cell proliferation and neovascularization. Front. Cardiovasc. Med. 2022;9:965965. doi: 10.3389/fcvm.2022.965965. PubMed DOI PMC

Ausprunk D.H., Knighton D.R., Folkman J. Vascularization of normal and neoplastic tissues grafted to the chick chorioallantois. Am. J. Pathol. 1975;79:597–618. PubMed PMC

Kuri P.M., Pion E., Mahl L., Kainz P., Schwarz S., Brochhausen C., Aung T., Haerteis S. Deep learning-based image analysis for the quantification of tumor-induced angiogenesis in the 3D in vivo tumor model—Establishment and addition to Laser Speckle Contrast Imaging (LSCI) Cells. 2022;11:2321. doi: 10.3390/cells11152321. PubMed DOI PMC