Coriolus versicolor (CV), known in traditional Chinese medicine for over 2000 years, is currently used in China and Japan to reduce chemotherapy or radiotherapy side effects in cancer patients. Despite extensive research, its effects still need improvement. This study aimed to determine if combining CV extract with LY294002, an inhibitor of the phosphatidylinositol-3-kinase (PI3K) signalling pathway, enhances cancer cell treatment, potentially leading to a novel therapeutic approach. Three human cancer cell lines (MCF-7, HeLa, and A549) were treated with CV extract alone or combined with LY294002. Cell viability was assessed using MTT assays. Then, HeLa and MCF-7 cells most sensitive to the co-treatment were used to evaluate colony formation, apoptosis, cell cycle, cell migration and invasion, and phospho-PI3K expression. The results demonstrated that LY294002 enhanced the CV extract's anti-tumour effects by reducing cell viability and colony formation. The combined treatment with CV extract and LY294002 more effectively induced G0/G1 cell cycle arrest, promoted apoptosis, reduced cell invasion and migration, and inhibited phospho-PI3K expression compared to each agent alone. This study highlights the potent cytotoxic enhancement between CV extract and LY294002 on cancer cells, primarily by inhibiting phospho-PI3K expression. These findings suggest promising avenues for developing novel combination therapies targeting cancer.

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentska 573 Str 532 10 Pardubice Czech Republic

Department of Immunology Faculty of Biological and Veterinary Sciences Nicolaus Copernicus University Lwowska 1 Str 87 100 Toruń Poland

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Jing Y., Zhang S., Li M., Ma Y., Zheng Y., Zhang D., Wu L. Research Progress on the Extraction, Structure, and Bioactivities of Polysaccharides from Coriolus versicolor. Foods. 2022;11:2126. doi: 10.3390/foods11142126. PubMed DOI PMC

Chen Y., Yao F., Ming K., Wang D., Hu Y., Liu J. Polysaccharides from Traditional Chinese Medicines: Extraction, Purification, Modification, and Biological Activity. Molecules. 2016;21:1705. doi: 10.3390/molecules21121705. PubMed DOI PMC

Habtemariam S. Trametes versicolor (Synn. Coriolus versicolor) Polysaccharides in Cancer Therapy: Targets and Efficacy. Biomedicines. 2020;8:135. doi: 10.3390/biomedicines8050135. PubMed DOI PMC

Bains A., Chawla P., Kaur S., Najda A., Fogarasi M., Fogarasi S. Bioactives from Mushroom: Health Attributes and Food Industry Applications. Materials. 2021;14:7640. doi: 10.3390/ma14247640. PubMed DOI PMC

Jędrzejewski T., Pawlikowska M., Sobocińska J., Wrotek S. COVID-19 and Cancer Diseases-The Potential of Coriolus versicolor Mushroom to Combat Global Health Challenges. Int. J. Mol. Sci. 2023;24:4864. doi: 10.3390/ijms24054864. PubMed DOI PMC

Saleh M.H., Rashedi I., Keating A. Immunomodulatory Properties of Coriolus versicolor: The Role of Polysaccharopeptide. Front. Immunol. 2017;8:1087. doi: 10.3389/fimmu.2017.01087. PubMed DOI PMC

He Z., Lin J., He Y., Liu S. Polysaccharide-Peptide from Trametes versicolor: The Potential Medicine for Colorectal Cancer Treatment. Biomedicines. 2022;10:2841. doi: 10.3390/biomedicines10112841. PubMed DOI PMC

Maehara Y., Tsujitani S., Saeki H., Oki E., Yoshinaga K., Emi Y., Morita M., Kohnoe S., Kakeji Y., Yano T., et al. Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN(®)): Review of development and future perspectives. Surg. Today. 2012;42:8–28. doi: 10.1007/s00595-011-0075-7. PubMed DOI PMC

Torkelson C.J., Sweet E., Martzen M.R., Sasagawa M., Wenner C.A., Gay J., Putiri A., Standish L.J. Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer. ISRN Oncol. 2012;2012:251632. doi: 10.5402/2012/251632. PubMed DOI PMC

Chang Y., Zhang M., Jiang Y., Liu Y., Luo H., Hao C., Zeng P., Zhang L. Preclinical and clinical studies of Coriolus versicolor polysaccharopeptide as an immunotherapeutic in China. Discov. Med. 2017;23:207–219. PubMed

Pilkington K., Wieland L.S., Teng L., Jin X.Y., Storey D., Liu J.P. Coriolus (Trametes) versicolor mushroom to reduce adverse effects from chemotherapy or radiotherapy in people with colorectal cancer. Cochrane Database Syst. Rev. 2022;11:CD012053. doi: 10.1002/14651858.CD012053.pub2. PubMed DOI PMC

Sivanesan I., Muthu M., Gopal J., Oh J.W. Mushroom Polysaccharide-Assisted Anticarcinogenic Mycotherapy: Reviewing Its Clinical Trials. Molecules. 2022;27:4090. doi: 10.3390/molecules27134090. PubMed DOI PMC

Rascio F., Spadaccino F., Rocchetti M.T., Castellano G., Stallone G., Netti G.S., Ranieri E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers. 2021;13:3949. doi: 10.3390/cancers13163949. PubMed DOI PMC

Castel P., Toska E., Engelman J.A., Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. Nat. Cancer. 2021;2:587–597. doi: 10.1038/s43018-021-00218-4. PubMed DOI PMC

Wang Y., Kuramitsu Y., Baron B., Kitagawa T., Tokuda K., Akada J., Maehara S.I., Maehara Y., Nakamura K. PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Int. J. Oncol. 2017;50:606–612. doi: 10.3892/ijo.2016.3804. PubMed DOI

Meng D., He W., Zhang Y., Liang Z., Zheng J., Zhang X., Zheng X., Zhan P., Chen H., Li W., et al. Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review) Pharmacol. Res. 2021;173:105900. doi: 10.1016/j.phrs.2021.105900. PubMed DOI

Abdallah M.E., El-Readi M.Z., Althubiti M.A., Almaimani R.A., Ismail A.M., Idris S., Refaat B., Almalki W.H., Babakr A.T., Mukhtar M.H., et al. Tamoxifen and the PI3K Inhibitor: LY294002 Synergistically Induce Apoptosis and Cell Cycle Arrest in Breast Cancer MCF-7 Cells. Molecules. 2020;25:3355. doi: 10.3390/molecules25153355. PubMed DOI PMC

Guney Eskiler G., Ozturk M. Therapeutic potential of the PI3K inhibitor LY294002 and PARP inhibitor Talazoparib combination in BRCA-deficient triple negative breast cancer cells. Cell. Signal. 2022;91:110229. doi: 10.1016/j.cellsig.2021.110229. PubMed DOI

Huang A., Zeng P., Li Y., Lu W., Lai Y. LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering with PI3K/Akt Signaling Pathway. Front. Oncol. 2021;11:782065. doi: 10.3389/fonc.2021.782065. PubMed DOI PMC

Badinloo M., Esmaeili Mahani S. Combined Application of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Inhibitors Suppresses Cell Growth and Promotes Apoptosis in Human Lung Cancer Cell Lines. Int. J. Cancer. Manag. 2016;9:e3433. doi: 10.17795/ijcp-3433. DOI

Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74:229–263. doi: 10.3322/caac.21834. PubMed DOI

Biological Evaluation of Medical Devices. Part 5: Tests for in Vitro Cytotoxicity. International Organization for Standardization; Geneva, Switzerland: 2021.

Standish L.J., Wenner C.A., Sweet E.S., Bridge C., Nelson A., Martzen M., Novack J., Torkelson C. Trametes versicolor mushroom immune therapy in breast cancer. J. Soc. Integr. Oncol. 2008;6:122–128. PubMed PMC

Roca-Lema D., Martinez-Iglesias O., Fernández de Ana Portela C., Rodríguez-Blanco A., Valladares-Ayerbes M., Díaz-Díaz A., Casas-Pais A., Prego C., Figueroa A. In Vitro Anti-proliferative and Anti-invasive Effect of Polysaccharide-rich Extracts from Trametes Versicolor and Grifola Frondosa in Colon Cancer Cells. Int. J. Med. Sci. 2019;16:231–240. doi: 10.7150/ijms.28811. PubMed DOI PMC

Jędrzejewski T., Sobocińska J., Pawlikowska M., Dzialuk A., Wrotek S. Extract from the Coriolus versicolor Fungus as an Anti-Inflammatory Agent with Cytotoxic Properties against Endothelial Cells and Breast Cancer Cells. Int. J. Mol. Sci. 2020;21:9063. doi: 10.3390/ijms21239063. PubMed DOI PMC

Winder M., Bulska-Będkowska W., Chudek J. The use of Hericium erinaceus and Trametes versicolor extracts in supportive treatment in oncology. Acta Pharm. 2021;71:1–16. doi: 10.2478/acph-2021-0007. PubMed DOI

Lowenthal R., Taylor M., Gidden J.A., Heflin B., Lay J.O., Jr., Avaritt N., Tackett A.J., Urbaniak A. The mycelium of the Trametes versicolor synn. Coriolus versicolor (Turkey tail mushroom) exhibit anti-melanoma activity in vitro. Biomed. Pharmacother. 2023;161:114424. doi: 10.1016/j.biopha.2023.114424. PubMed DOI PMC

Liu R., Chen Y., Liu G., Li C., Song Y., Cao Z., Li W., Hu J., Lu C., Liu Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11:797. doi: 10.1038/s41419-020-02998-6. PubMed DOI PMC

Curigliano G., Shah R.R. Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology. Drug. Saf. 2019;42:247–262. doi: 10.1007/s40264-018-0778-4. PubMed DOI

Coleman N., Moyers J.T., Harbery A., Vivanco I., Yap T.A. Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine. Pharmgenomics. Pers. Med. 2021;14:1517–1535. doi: 10.2147/PGPM.S305068. PubMed DOI PMC

Jędrzejewski T., Sobocińska J., Pawlikowska M., Dzialuk A., Wrotek S. Dual Effect of the Extract from the Fungus Coriolus versicolor on Lipopolysaccharide-Induced Cytokine Production in RAW 264.7 Macrophages Depending on the Lipopolysaccharide Concentration. J. Inflamm. Res. 2022;15:3599–3611. doi: 10.2147/JIR.S364945. PubMed DOI PMC

Blagodatski A., Yatsunskaya M., Mikhailova V., Tiasto V., Kagansky A., Katanaev V.L. Medicinal mushrooms as an attractive new source of natural compounds for future cancer therapy. Oncotarget. 2018;9:29259–29274. doi: 10.18632/oncotarget.25660. PubMed DOI PMC

Gomes N.P., Frederick B., Jacobsen J.R., Chapnick D., Su T.T. A High Throughput Screen with a Clonogenic Endpoint to Identify Radiation Modulators of Cancer. Radiat. Res. 2023;199:132–147. doi: 10.1667/RADE-22-00086.1. PubMed DOI PMC

Ricciardi M.R., Licchetta R., Mirabilii S., Scarpari M., Parroni A., Fabbri A.A., Cescutti P., Reverberi M., Fanelli C., Tafuri A. Preclinical Antileukemia Activity of Tramesan: A Newly Identified Bioactive Fungal Metabolite. Oxid. Med. Cell. Longev. 2017;2017:5061639. doi: 10.1155/2017/5061639. PubMed DOI PMC

Jiménez-Medina E., Berruguilla E., Romero I., Algarra I., Collado A., Garrido F., Garcia-Lora A. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis. BMC Cancer. 2008;8:78. doi: 10.1186/1471-2407-8-78. PubMed DOI PMC

Wan J.M., Sit W.H., Yang X., Jiang P., Wong L.L. Polysaccharopeptides Derived from Coriolus Versicolor Potentiate the S-Phase Specific Cytotoxicity of Camptothecin (CPT) on Human Leukemia HL-60 Cells. Chin. Med. 2010;5:16. doi: 10.1186/1749-8546-5-16. PubMed DOI PMC

Hsieh T.C., Wu P., Park S., Wu J.M. Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signaling regulatory protein expression by water extracts of I’m-Yunity (PSP) BMC Complement. Altern. Med. 2006;6:30. doi: 10.1186/1472-6882-6-30. PubMed DOI PMC

Lu X.X., Cao L.Y., Chen X., Xiao J., Zou Y., Chen Q. PTEN Inhibits Cell Proliferation, Promotes Cell Apoptosis, and Induces Cell Cycle Arrest via Downregulating the PI3K/AKT/hTERT Pathway in Lung Adenocarcinoma A549 Cells. Biomed. Res. Int. 2016;2016:2476842. doi: 10.1155/2016/2476842. PubMed DOI PMC

Pucci B., Kasten M., Giordano A. Cell cycle and apoptosis. Neoplasia. 2000;2:291–299. doi: 10.1038/sj.neo.7900101. PubMed DOI PMC

Lau C.B., Ho C.Y., Kim C.F., Leung K.N., Fung K.P., Tse T.F., Chan H.H., Chow M.S. Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis. Life Sci. 2004;75:797–808. doi: 10.1016/j.lfs.2004.04.001. PubMed DOI

Hirahara N., Fujioka M., Edamatsu T., Fujieda A., Sekine F., Wada T., Tanaka T. Protein-bound polysaccharide-K (PSK) induces apoptosis and inhibits proliferation of promyelomonocytic leukemia HL-60 cells. Anticancer. Res. 2011;31:2733–2738. PubMed

Luo K.W., Yue G.G., Ko C.H., Lee J.K., Gao S., Li L.F., Li G., Fung K.P., Leung P.C., Lau C.B. In vivo and in vitro anti-tumor and anti-metastasis effects of Coriolus versicolor aqueous extract on mouse mammary 4T1 carcinoma. Phytomedicine. 2014;21:1078–1087. doi: 10.1016/j.phymed.2014.04.020. PubMed DOI

Jiang H., Fan D., Zhou G., Li X., Deng H. Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo. J. Exp. Clin. Cancer Res. 2010;29:34. doi: 10.1186/1756-9966-29-34. PubMed DOI PMC

Novikov N.M., Zolotaryova S.Y., Gautreau A.M., Denisov E.V. Mutational drivers of cancer cell migration and invasion. Br. J. Cancer. 2021;124:102–114. doi: 10.1038/s41416-020-01149-0. PubMed DOI PMC

Liu P., Xu B., Li J., Lu H. LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway. Biochem. Biophys. Res. Commun. 2008;377:187–190. doi: 10.1016/j.bbrc.2008.09.094. PubMed DOI

Shukla S., Maclennan G.T., Hartman D.J., Fu P., Resnick M.I., Gupta S. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int. J. Cancer. 2007;121:1424–1432. doi: 10.1002/ijc.22862. PubMed DOI

Duarte A., Silveira G.G., Soave D.F., Costa J.P.O., Silva A.R. The Role of the LY294002—A Non-Selective Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) Pathway- in Cell Survival and Proliferation in Cell Line SCC-25. Asian. Pac. J. Cancer. Prev. 2019;20:3377–3383. doi: 10.31557/APJCP.2019.20.11.3377. PubMed DOI PMC

Zhou Y., Zhu L.B., Peng A.F., Wang T.F., Long X.H., Gao S., Zhou R.P., Liu Z.L. LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3-kinase/Akt/fatty acid synthase signaling pathway in vitro. Mol. Med. Rep. 2015;11:1352–1357. doi: 10.3892/mmr.2014.2787. PubMed DOI

Teranishi F., Takahashi N., Gao N., Akamo Y., Takeyama H., Manabe T., Okamoto T. Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Sci. 2009;100:770–777. doi: 10.1111/j.1349-7006.2009.01084.x. PubMed DOI PMC

Zhang H., Morisaki T., Matsunaga H., Sato N., Uchiyama A., Hashizume K., Nagumo F., Tadano J., Katano M. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs. Clin. Exp. Metastasis. 2000;18:343–352. doi: 10.1023/a:1010897432244. PubMed DOI

Matsunaga K., Ohhara M., Oguchi Y., Iijima H., Kobayashi H. Antimetastatic effect of PSK, a protein-bound polysaccharide, against the B16-BL6 mouse melanoma. Invasion Metastasis. 1996;16:27–38. PubMed

Esposito A., Viale G., Curigliano G. Safety, Tolerability, and Management of Toxic Effects of Phosphatidylinositol 3-Kinase Inhibitor Treatment in Patients with Cancer: A Review. JAMA Oncol. 2019;5:1347–1354. doi: 10.1001/jamaoncol.2019.0034. PubMed DOI

Jędrzejewski T., Sobocińska J., Maciejewski B., Spisz P., Walczak-Skierska J., Pomastowski P., Wrotek S. In vitro treatment of triple-negative breast cancer cells with an extract from the Coriolus versicolor mushroom changes macrophage properties related to tumorigenesis. Immunol. Res. 2025;73:14. doi: 10.1007/s12026-024-09574-6. PubMed DOI