{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:22:07Z","timestamp":1783002127259,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"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>Photodynamic therapy (PDT) is a light-based cancer therapy approach that has shown promising results in treating various malignancies. Growing evidence indicates that cancer stem cells (CSCs) are implicated in tumor recurrence, metastasis, and cancer therapy resistance in colorectal cancer (CRC); thus, targeting these cells can ameliorate the prognosis of affected patients. Based on our bioinformatics results, SOX2 overexpression is significantly associated with inferior disease-specific survival and worsened the progression-free interval of CRC patients. Our results demonstrate that zinc phthalocyanine (ZnPc)-PDT with 12 J\/cm2 or 24 J\/cm2 irradiation can substantially decrease tumor migration via downregulating MMP9 and ROCK1 and inhibit the clonogenicity of SW480 cells via downregulating CD44 and SOX2. Despite inhibiting clonogenicity, ZnPc-PDT with 12 J\/cm2 irradiation fails to downregulate CD44 expression in SW480 cells. Our results indicate that ZnPc-PDT with 12 J\/cm2 or 24 J\/cm2 irradiation can substantially reduce the cell viability of SW480 cells and stimulate autophagy in the tumoral cells. Moreover, our results show that ZnPc-PDT with 12 J\/cm2 or 24 J\/cm2 irradiation can substantially arrest the cell cycle at the sub-G1 level, stimulate the intrinsic apoptosis pathway via upregulating caspase-3 and caspase-9 and downregulating Bcl-2. Indeed, our bioinformatics results show considerable interactions between the studied CSC-related genes with the studied migration- and apoptosis-related genes. Collectively, the current study highlights the potential role of ZnPc-PDT in inhibiting stemness and CRC development, which can ameliorate the prognosis of CRC patients.<\/jats:p>","DOI":"10.3390\/molecules26226877","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"6877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Photodynamic Therapy with Zinc Phthalocyanine Inhibits the Stemness and Development of Colorectal Cancer: Time to Overcome the Challenging Barriers?"],"prefix":"10.3390","volume":"26","author":[{"given":"Mahsa","family":"Gholizadeh","sequence":"first","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3655-2515","authenticated-orcid":false,"given":"Mohammad Amin","family":"Doustvandi","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4107-9689","authenticated-orcid":false,"given":"Fateme","family":"Mohammadnejad","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4865-8779","authenticated-orcid":false,"given":"Mahdi Abdoli","family":"Shadbad","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"},{"name":"Student Research Committee, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habib","family":"Tajalli","sequence":"additional","affiliation":[{"name":"Biophotonic Research Center, Islamic Azad University, Tabriz Branch, Tabriz 51579-44533, Iran"},{"name":"Research Institute for Applied Physics and Astronomy, University of Tabriz, Tabriz 51666-16471, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7014-6828","authenticated-orcid":false,"given":"Oronzo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Argentiero","sequence":"additional","affiliation":[{"name":"Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7814-7318","authenticated-orcid":false,"given":"Nicola","family":"Silvestris","sequence":"additional","affiliation":[{"name":"Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), 70124 Bari, Italy"},{"name":"Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8642-6795","authenticated-orcid":false,"given":"Behzad","family":"Baradaran","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"},{"name":"Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1002\/bjs.7653","article-title":"Outcomes following surgery for colorectal cancer with synchronous peritoneal metastases","volume":"98","author":"Mulsow","year":"2011","journal-title":"Br. J. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3322\/caac.20107","article-title":"Global cancer statistics","volume":"61","author":"Jemal","year":"2011","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.ijrobp.2006.06.015","article-title":"Feasibility and efficacy of high-dose three-dimensional-conformal radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies\u2014mature results of the French Phase II RTF-1 trial","volume":"66","author":"Mornex","year":"2006","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nrc1071","article-title":"Photodynamic therapy for cancer","volume":"3","author":"Dolmans","year":"2003","journal-title":"Nat. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/jnci\/90.12.889","article-title":"Photodynamic therapy","volume":"90","author":"Dougherty","year":"1998","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6597","DOI":"10.1039\/C6CS00271D","article-title":"Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy","volume":"45","author":"Zhou","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1010428317734691","DOI":"10.1177\/1010428317734691","article-title":"Targeted photodynamic therapy as potential treatment modality for the eradication of colon cancer and colon cancer stem cells","volume":"39","author":"Hodgkinson","year":"2017","journal-title":"Tumor Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9541","DOI":"10.1007\/s11033-020-05952-z","article-title":"siRNA-mediated silencing of CD44 delivered by Jet Pei enhanced Doxorubicin chemo sensitivity and altered miRNA expression in human breast cancer cell line (MDA-MB468)","volume":"47","author":"Vahidian","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174147","DOI":"10.1016\/j.ejphar.2021.174147","article-title":"The role of CD44 in cancer chemoresistance: A concise review","volume":"903","author":"Yaghobi","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1002\/jcp.30063","article-title":"The oncogenic potential of NANOG: An important cancer induction mediator","volume":"236","author":"Najafzadeh","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Derakhshani, A., Rostami, Z., Safarpour, H., Shadbad, M.A., Nourbakhsh, N.S., Argentiero, A., Taefehshokr, S., Tabrizi, N.J., Kooshkaki, O., and Astamal, R.V. (2021). From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy. Molecules, 26.","DOI":"10.3390\/molecules26082278"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.clcc.2017.01.011","article-title":"The identifications and clinical implications of cancer stem cells in colorectal cancer","volume":"16","author":"Wahab","year":"2017","journal-title":"Clin. Colorectal Cancer."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-016-2509-5","article-title":"SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer","volume":"16","author":"Lundberg","year":"2016","journal-title":"BMC Cancer."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcancer.2019.08.007","article-title":"SOX2 in development and cancer biology","volume":"67","author":"Novak","year":"2020","journal-title":"Sem. Cancer Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jphotobiol.2017.09.020","article-title":"The interaction between the light source dose and caspase-dependent and-independent apoptosis in human SK-MEL-3 skin cancer cells following photodynamic therapy with zinc phthalocyanine: A comparative study","volume":"176","author":"Doustvandi","year":"2017","journal-title":"J. Photochem. Photobiol. B. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.pdpdt.2019.08.027","article-title":"Photodynamic therapy using zinc phthalocyanine with low dose of diode laser combined with doxorubicin is a synergistic combination therapy for human SK-MEL-3 melanoma cells","volume":"28","author":"Doustvandi","year":"2019","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.biocel.2019.02.010","article-title":"Targeting cancer stem cells as therapeutic approach in the treatment of colorectal cancer","volume":"110","author":"Liu","year":"2019","journal-title":"Int. J. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111436","DOI":"10.1016\/j.biopha.2021.111436","article-title":"PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines","volume":"138","author":"Lotfinejad","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","first-page":"211","article-title":"CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion","volume":"41","author":"Cho","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_21","first-page":"339","article-title":"shRNA against CD44 inhibits cell proliferation, invasion and migration, and promotes apoptosis of colon carcinoma cells","volume":"27","author":"Park","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3389\/fonc.2019.00309","article-title":"The prognostic and clinical value of CD44 in colorectal cancer: A meta-analysis","volume":"9","author":"Wang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-36251-0","article-title":"Sox2 is associated with cancer stem-like properties in colorectal cancer","volume":"8","author":"Takeda","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"98635","DOI":"10.18632\/oncotarget.21709","article-title":"Sox2 modulates motility and enhances progression of colorectal cancer via the Rho-ROCK signaling pathway","volume":"8","author":"Zheng","year":"2017","journal-title":"Oncotarget."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Han, X., Fang, X., Lou, X., Hua, D., Ding, W., Foltz, G., Hood, L., Yuan, Y., and Lin, B. (2012). Silencing SOX2 induced mesenchymal-epithelial transition and its expression predicts liver and lymph node metastasis of CRC patients. PLoS ONE., 7.","DOI":"10.1371\/journal.pone.0041335"},{"key":"ref_26","first-page":"1","article-title":"Functional characterization of SOX2 as an anticancer target","volume":"5","author":"Zhang","year":"2020","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"152769","DOI":"10.1016\/j.prp.2019.152769","article-title":"The association of SOX2 with clinical features and prognosis in colorectal cancer: A meta-analysis","volume":"216","author":"Zhang","year":"2020","journal-title":"Pathol. Res. Pract."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"383027","DOI":"10.1155\/2014\/383027","article-title":"Multiorganelle localization of metallated phthalocyanine photosensitizer in colorectal cancer cells (DLD-1 and CaCo-2) enhances efficacy of photodynamic therapy","volume":"2014","author":"Sekhejane","year":"2014","journal-title":"Int. J. Photoenergy"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ejmech.2018.03.077","article-title":"A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo-photodynamic therapy","volume":"151","author":"Huang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e201800114","DOI":"10.1002\/jbio.201800114","article-title":"Zinc pthalocyanine-loaded chitosan\/mPEG-PLA nanoparticles-mediated photodynamic therapy for the treatment of cutaneous squamous cell carcinoma","volume":"11","author":"Keyal","year":"2018","journal-title":"J. Biophotonics"},{"key":"ref_31","first-page":"534","article-title":"Novel zinc-and silicon-phthalocyanines as photosensitizers for photodynamic therapy of cholangiocarcinoma","volume":"42","author":"Schmidt","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20652","DOI":"10.1039\/C9RA03911B","article-title":"Synthesis and biological evaluation of an epidermal growth factor receptor-targeted peptide-conjugated phthalocyanine-based photosensitiser","volume":"9","author":"Xue","year":"2019","journal-title":"RSC Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.nano.2018.02.005","article-title":"Zinc phthalocyanine encapsulated in polymer micelles as a potent photosensitizer for the photodynamic therapy of osteosarcoma","volume":"14","author":"Yu","year":"2018","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"953","DOI":"10.3892\/ijo.2017.3854","article-title":"Novel zinc phthalocyanine as a promising photosensitizer for photodynamic treatment of esophageal cancer","volume":"50","author":"Kuzyniak","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17193","DOI":"10.1021\/acsami.0c00375","article-title":"Sorafenib-conjugated zinc phthalocyanine based nanocapsule for trimodal therapy in an orthotopic hepatocellular carcinoma xenograft mouse model","volume":"12","author":"Yu","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.jphotobiol.2016.06.017","article-title":"Effects of continuous wave and fractionated diode laser on human fibroblast cancer and dermal normal cells by zinc phthalocyanine in photodynamic therapy: A comparative study","volume":"161","author":"Navaeipour","year":"2016","journal-title":"J. Photochem. Photobiol. B. Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/22\/6877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:27Z","timestamp":1760167827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/22\/6877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":36,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["molecules26226877"],"URL":"https:\/\/doi.org\/10.3390\/molecules26226877","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}