{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:16:18Z","timestamp":1760058978695,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Ministry of Health and Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HF20C0030"],"award-info":[{"award-number":["HF20C0030"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer remains a significant global health concern. In this study, we investigated the anticancer potential of Circaea mollis Siebold &amp; Zucc. (CS&amp;Z), a traditional medicinal plant known for its anti-inflammatory, anti-arthritic, and antioxidant properties, in the treatment of colorectal cancer. We found that CS&amp;Z induces apoptosis and G1\/S phase cell cycle arrest in colorectal cancer cells, primarily through the suppression of the proto-oncogene c-Myc. Specifically, the depletion of RPL5, a ribosomal protein associated with c-Myc regulation, reversed the suppression of c-Myc by CS&amp;Z. Additionally, when co-administered with the standard chemotherapeutic agents doxorubicin and 5-fluorouracil, CS&amp;Z demonstrated synergistic effects, thereby further emphasizing its potential efficacy as a therapeutic option for the treatment of colorectal cancer. Moreover, the constituents of CS&amp;Z, detected through liquid chromatography\u2013mass spectrometry analysis, reportedly exhibit anticancer activities. Taken together, our findings suggest that CS&amp;Z holds promise as a natural product capable of modulating oncogenic signaling in colorectal cancer and may serve as a complementary agent in future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26104664","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T11:31:49Z","timestamp":1747135909000},"page":"4664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circaea mollis Siebold &amp; Zucc. Induces Apoptosis in Colorectal Cancer Cells by Inhibiting c-Myc Through the Mediation of RPL5"],"prefix":"10.3390","volume":"26","author":[{"given":"So-Mi","family":"Park","sequence":"first","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanyeong","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye-Rin","family":"Park","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seok Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5644-5960","authenticated-orcid":false,"given":"Ji Hoon","family":"Jung","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Cheol","family":"Na","sequence":"additional","affiliation":[{"name":"Metropolitan Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1314-2537","authenticated-orcid":false,"given":"Daeho","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3919-4597","authenticated-orcid":false,"given":"Hyungsuk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Korean Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4996-9053","authenticated-orcid":false,"given":"Hyeung-Jin","family":"Jang","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s10354-022-00975-6","article-title":"Colorectal cancer","volume":"173","author":"Zhang","year":"2023","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ionescu, V.A., Gheorghe, G., Bacalbasa, N., Chiotoroiu, A.L., and Diaconu, C. (2023). Colorectal Cancer: From Risk Factors to Oncogenesis. Medicina, 59.","DOI":"10.20944\/preprints202308.1837.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1136\/gutjnl-2013-304701","article-title":"Obesity and colorectal cancer","volume":"62","author":"Bardou","year":"2013","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.3748\/wjg.v29.i8.1289","article-title":"Early-onset colorectal cancer: A review of current knowledge","volume":"29","author":"Saraiva","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1038\/s41467-019-11447-8","article-title":"LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc","volume":"10","author":"Tang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sawicki, T., Ruszkowska, M., Danielewicz, A., Nied\u017awiedzka, E., Ar\u0142ukowicz, T., and Przyby\u0142owicz, K.E. (2021). A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis. Cancers, 13.","DOI":"10.3390\/cancers13092025"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.tcb.2022.11.003","article-title":"Targeting ferroptosis to treat colorectal cancer","volume":"33","author":"Yan","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105374","DOI":"10.1016\/j.phrs.2020.105374","article-title":"Dendritic cell vaccine therapy for colorectal cancer","volume":"164","author":"Wooster","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107447","DOI":"10.1016\/j.pharmthera.2019.107447","article-title":"5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future","volume":"206","author":"Vodenkova","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ko, H.M., Jee, W., Park, D.-i., Kim, K.-I., Jung, J.H., and Jang, H.-J. (2022). The Antitumor Effect of Timosaponin A3 through c-Myc Inhibition in Colorectal Cancer Cells and Combined Treatment Effect with 5-FU or Doxorubicin. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911900"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jee, W., Ko, H.M., Park, D.-I., Park, Y.-R., Park, S.-M., Kim, H., Na, Y.-C., Jung, J.H., and Jang, H.-J. (2023). Momordicae Semen inhibits migration and induces apoptotic cell death by regulating c-Myc and CNOT2 in human pancreatic cancer cells. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-39840-w"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12943-022-01622-9","article-title":"E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predictor for chemotherapy response in colorectal cancer","volume":"21","author":"Wang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Park, S.M., Jee, W., Park, Y.R., Kim, H., Na, Y.C., Jung, J.H., and Jang, H.J. (2023). Euonymus sachalinensis Induces Apoptosis by Inhibiting the Expression of c-Myc in Colon Cancer Cells. Molecules, 28.","DOI":"10.3390\/molecules28083473"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ko, H.M., Jee, W., Lee, D., Jang, H.J., and Jung, J.H. (2022). Ophiopogonin D increase apoptosis by activating p53 via ribosomal protein L5 and L11 and inhibiting the expression of c-Myc via CNOT2. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.974468"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1002\/ptr.6878","article-title":"Ribosomal protein L5 mediated inhibition of c-Myc is critically involved in sanggenon G induced apoptosis in non-small lung cancer cells","volume":"35","author":"Park","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wy\u017cewski, Z., \u015awitlik, W., Mielcarska, M.B., and Gregorczyk-Zboroch, K.P. (2021). The Role of Bcl-xL Protein in Viral Infections. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041956"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Jung, J.H., Lee, D., Ko, H.M., and Jang, H.-J. (2021). Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53. Biomolecules, 11.","DOI":"10.3390\/biom11101492"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0165-6147(03)00026-9","article-title":"Cell-cycle dysregulation and anticancer therapy","volume":"24","author":"Stewart","year":"2003","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114450","DOI":"10.1016\/j.jep.2021.114450","article-title":"The potential and outgoing trends in traditional, phytochemical, economical, and ethnopharmacological importance of family Onagraceae: A comprehensive review","volume":"281","author":"Shawky","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.ympev.2009.09.009","article-title":"Molecular phylogeny, divergence time estimates, and historical biogeography of Circaea (Onagraceae) in the Northern Hemisphere","volume":"53","author":"Xie","year":"2009","journal-title":"Mol. Phylogenetics Evol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Park, J.H., Son, Y.J., Lee, C.H., Nho, C.W., and Yoo, G. (2020). Circaea mollis Siebold & Zucc. Alleviates postmenopausal osteoporosis in a mouse model via the BMP-2\/4\/Runx2 pathway. BMC Complement. Med. Ther., 20.","DOI":"10.1186\/s12906-020-02914-7"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jep.2018.04.051","article-title":"Anti-arthritic activities of ethanol extracts of Circaea mollis Sieb. & Zucc. (whole plant) in rodents","volume":"225","author":"Zhang","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4916","DOI":"10.1038\/onc.2013.430","article-title":"Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex","volume":"33","author":"Liao","year":"2014","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1104\/pp.126.2.485","article-title":"Flavonoid Biosynthesis. A Colorful Model for Genetics, Biochemistry, Cell Biology, and Biotechnology","volume":"126","year":"2001","journal-title":"Plant Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yu, H., Li, J., Hu, X., Feng, J., Wang, H., and Xiong, F. (2019). Protective effects of cynaroside on oxidative stress in retinal pigment epithelial cells. J. Biochem. Mol. Toxicol., 33.","DOI":"10.1002\/jbt.22352"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ji, J., Wang, Z., Sun, W., Li, Z., Cai, H., Zhao, E., and Cui, H. (2021). Effects of Cynaroside on Cell Proliferation, Apoptosis, Migration and Invasion though the MET\/AKT\/mTOR Axis in Gastric Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212125"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8704146","DOI":"10.1155\/2020\/8704146","article-title":"Isoorientin Inhibits Inflammation in Macrophages and Endotoxemia Mice by Regulating Glycogen Synthase Kinase 3\u03b2","volume":"2020","author":"Li","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, H., Yuan, L., Li, X., Luo, Y., Zhang, Z., and Li, J. (2021). Isoorientin Attenuated the Pyroptotic Hepatocyte Damage Induced by Benzo[a]pyrene via ROS\/NF-\u03baB\/NLRP3\/Caspase-1 Signaling Pathway. Antioxidants, 10.","DOI":"10.3390\/antiox10081275"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.fct.2012.11.048","article-title":"MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells","volume":"53","author":"Yuan","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1080\/09168451.2019.1702871","article-title":"Orientin suppresses oxidized low-density lipoproteins induced inflammation and oxidative stress of macrophages in atherosclerosis","volume":"84","author":"Li","year":"2020","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_31","first-page":"4104595","article-title":"A Review on Medicinal Properties of Orientin","volume":"2016","author":"Lam","year":"2016","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Thangaraj, K., Balasubramanian, B., Park, S., Natesan, K., Liu, W., and Manju, V. (2019). Orientin Induces G0\/G1 Cell Cycle Arrest and Mitochondria Mediated Intrinsic Apoptosis in Human Colorectal Carcinoma HT29 Cells. Biomolecules, 9.","DOI":"10.3390\/biom9090418"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41420-023-01324-1","article-title":"Neuroprotective effect of astragalin via activating PI3K\/Akt-mTOR-mediated autophagy on APP\/PS1 mice","volume":"9","author":"Yang","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.fitote.2016.09.011","article-title":"A review on the pharmacological effects of vitexin and isovitexin","volume":"115","author":"He","year":"2016","journal-title":"Fitoterapia"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Llombart, V., and Mansour, M.R. (2022). Therapeutic targeting of \u201cundruggable\u201d MYC. EBioMedicine, 75.","DOI":"10.1016\/j.ebiom.2021.103756"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/bjh.14684","article-title":"Targeting anti-apoptotic BCL2 family proteins in haematological malignancies\u2014From pathogenesis to treatment","volume":"178","author":"Vogler","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Malumbres, M. (2014). Cyclin-dependent kinases. Genome Biol., 15.","DOI":"10.1186\/gb4184"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.phymed.2018.08.006","article-title":"Apoptosis and G2\/M cell cycle arrest induced by a timosaponin A3 from Anemarrhena asphodeloides Bunge on AsPC-1 pancreatic cancer cells","volume":"56","author":"Kim","year":"2019","journal-title":"Phytomedicine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4664\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:32:03Z","timestamp":1760031123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104664"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104664","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,5,13]]}}}