Anti-tumor and anti-metastatic effects of pentagalloyl glucose on fluorouracil-resistant colorectal cancer: Targeting on cancer stem cells and the epithelial-mesenchymal transition process

¼Å¡Òõè͵éÒ¹à¹×éͧ͡áÅлéͧ¡Ñ¹¡ÒÃá¾Ãè¡ÃШÒ¢ͧྐྵµÐ¡ÑÅâÅÍÔÅ¡ÅÙâ¤ÊµèÍÁÐàÃç§ÅÓäÊé·Õè·¹µèÍ¿ÅÙÍÍâÃÂÙÃÒ«ÔÅ: ÁØè§à»éÒ·Õèà«ÅÅìµé¹¡Óà¹Ô´ÁÐàÃç§áÅСÃкǹ¡ÒÃà»ÅÕè¹¼èÒ¹¢Í§àÂ×èͺؼÔÇáÅÐÁÕૹä¤ÁÍÅ

Name: Wen, Chengli

LCSH: Intestine, Large -- Cancer

LCSH: Pentagalloyl glucose

LCSH: Antineoplastic agents

LCSH: Antineoplastic agents -- Development

Abstract: Colorectal cancer (CRC) has a high incidence and mortality. According to the latest global cancer statistics, the incidence of CRC is approximately 10%, ranking third, while the mortality is about 9.4%, ranking second. An increasing number of CRCs are developing resistance to conventional chemotherapeutic agents such as 5-Fluorouracil (5-FU). Cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) process both contribute to cancer resistance and metastasis. Signal Transducer and Activator of Transcription 3 (STAT3) activation plays a crucial role in maintaining CSC stemness, the EMT process, and chemoresistance.ÿIn this study, Pentagalloyl glucose (PGG) was extracted from the seeds of Bouea macrophylla, and its anticancer activity against 5-FU-resistant CRC was evaluated through in vitro and in vivo experiments. We tested the inhibitory effect of PGG on the proliferation of 5-FU-resistant CRC using the Cell Counting Kit-8 (CCK-8) and clone formation assays. Moreover, the inhibitory effect of PGG on CSCs was confirmed by flow cytometry, measurement of sphere size, and staining of live and dead cells in 3D culture. In addition, scratch healing assay and transwell assay for testing the inhibitory effect of PGG on EMT-induced invasion and migration. Pathways for PGG intervention were examined at both the transcriptomic and protein levels. The inhibitory effects of PGG on tumor proliferation, CSCs, and the EMT process, and the promotion of tumor cell apoptosis in 5-FU-resistant CRC were verified in animal models. We established two animal models for the experiment: a subcutaneous tumor-forming model and a tail vein injection tumor metastasis model. This study found that PGG inhibits 5-FU-resistant CRC both in vivo and in vitro. Firstly, in two-dimensional (2D) and three-dimensional (3D) cell models, as well as an in vivo model, PGG inhibited the proliferation of CSCs. Secondly, PGG inhibited the EMT process both in vitro and vivo, suppressing invasion and metastasis in 5-FU-resistant CRC. Moreover, PGG induced apoptosis in cancer cells. Furthermore, PGG inhibited the Janus kinase 1/Janus kinase 3-signal transducer and activator of transcription 3 (JAK1/JAK3-STAT3) signaling pathway and STAT3 phosphorylation, as well as the expression of downstream proteins such as CSC-related markers (CD133, CD44 and leucine-rich repeat- containing G protein-coupled receptor, EMT-associated markers (N-cadherin, vimentin), and B-cell lymphoma-2 (Bcl-2), as confirmed by JAK1 and JAK3 inhibitors.ÿIn conclusion, PGG exerts antitumor activity against 5-FU-resistant CRC by inhibiting the JAK1/JAK3-STAT3 signaling pathway. This provides new insights into the treatment of 5-FU-resistant CRC and lays the groundwork for clinical research into PGG\'s potential as a therapeutic agent.

Abstract: ÁÐàÃç§ÅÓäÊéãË­è (Colorectal cancer; CRC) à»ç¹âä·ÕèÁÕÍغѵԡÒóìáÅÐÍѵÃÒ¡ÒÃàÊÕªÕÇÔµÊÙ§ â´Â¨Ò¡Ê¶ÔµÔâÅ¡ÅèÒÊØ´¾ºÇèÒ CRC ÁÕÍغѵԡÒóì¤Ô´à»ç¹»ÃÐÁÒ³ÃéÍÂÅÐ 10 (Íѹ´Ñº 3) áÅÐÁÕÍѵÃÒ¡ÒÃàÊÕªÕÇÔµÃéÍÂÅÐ 9.4 (Íѹ´Ñº 2) á¹Çâ¹éÁ¡Òô×é͵èÍÂÒà¤ÁպӺѴ àªè¹ 5-Fluorouracil (5-FU) ÁÕà¾ÔèÁÁÒ¡¢Öé¹ â´ÂÁջѨ¨ÑÂÊӤѭ ä´éá¡è à«ÅÅìµé¹¡Óà¹Ô´ÁÐàÃç§ (Cancer Stem Cells; CSCs) áÅСÃкǹ¡ÒÃà»ÅÕè¹¼èÒ¹¨Ò¡à«ÅÅìàÂ×èͺؼÔÇä»à»ç¹ª¹Ô´ÁÕૹä¤Áì (Epithelial-Mesenchymal Transition; EMT) «Öè§ÅéǹÊ觼ŵèͤÇÒÁÊÒÁÒö㹡ÒÃá¾Ãè¡ÃШÒÂáÅд×é͵èÍÂÒ ·Ñ駹Õé ¡ÒáÃеØ鹢ͧâ»ÃµÕ¹ STAT3 (Signal Transducer and Activator of Transcription 3) ÁÕº·ºÒ·ÊӤѭ㹡Òä§ÊÀÒ¾¢Í§ CSCs ¡ÒÃà¡Ô´ EMT áÅСÒô×é͵èÍÂÒ¡ÒÃÈÖ¡ÉÒ¹ÕéÁØ觻ÃÐàÁԹķ¸ÔìµéÒ¹ÁÐàÃ秢ͧྐྵµÐ¡ÑÅâÅÍÔÅ¡ÅÙâ¤Ê (Pentagalloyl glucose; PGG) «Öè§à»ç¹ÊÒøÃÃÁªÒµÔ·ÕèÊ¡Ñ´¨Ò¡àÁÅç´ÁлÃÒ§ (Bouea macrophylla) µèÍà«ÅÅìÁÐàÃç§ÅÓäÊé·Õè´×é͵èÍ 5-FU ·Ñé§ã¹ËÅÍ´·´ÅͧáÅÐã¹ÊѵÇì·´Åͧ ¡Ò÷´Åͧã¹ÃдѺà«ÅÅì»ÃСͺ´éÇ¡ÒÃÇÔà¤ÃÒÐËì¡ÒÃÂѺÂÑ駡ÒÃà¨ÃÔ­¢Í§à«ÅÅì´éǪش·´Êͺ CCK-8 áÅСÒÃÊÃéÒ§â¤âÅ¹Õ ÃÇÁ¶Ö§¡ÒûÃÐàÁÔ¹¼ÅµèÍ CSCs â´Âãªéâ¿Åä«âµàÁµÃÕ ¡ÒÃÇÑ´¢¹Ò´Êà¿ÕÂÃì áÅСÒÃÂéÍÁµÔ´ÊÕà«ÅÅì·ÕèÁÕ/äÁèÁÕªÕÇÔµã¹Ãкº 3 ÁÔµÔ ¹Í¡¨Ò¡¹Õé Âѧ»ÃÐàÁÔ¹¡ÒÃÂѺÂÑ駡ÒÃà¤Å×è͹·ÕèáÅСÒÃÃØ¡ÃÒ¹¢Í§à«ÅÅì¼èÒ¹¡Ò÷´Êͺ scratch assay áÅÐ transwell assayã¹ÃдѺâÁàÅ¡ØÅ ¾ºÇèÒ PGG ÊÒÁÒöÂѺÂÑ駡ÒÿÍÊâ¿ÃÕàŪѹ¢Í§ STAT3 áÅÐÅ´¡ÒÃáÊ´§ÍÍ¡¢Í§â»ÃµÕ¹ã¹àÊé¹·Ò§ JAK1/JAK3-STAT3 ä´éá¡è µÑǺ觪Õé CSCs (CD133, CD44, LGR5) µÑǺ觪Õé EMT (N-cadherin, vimentin) áÅÐâ»ÃµÕ¹µéÒ¹¡ÒõÒ¢ͧà«ÅÅì Bcl-2 â´Â¼Å´Ñ§¡ÅèÒÇÊÍ´¤Åéͧ¡Ñº¡ÒÃãªéÊÒÃÂѺÂÑé§ JAK1 áÅÐ JAK3 㹡Ò÷´Åͧã¹ÊѵÇì ä´é¾Ñ²¹ÒẺ¨ÓÅͧÁÐàÃç§ 2 ÃٻẺ ä´éá¡è ¡ÒáèÍà¹×éͧ͡ãµé¼ÔÇ˹ѧ áÅСÒÃá¾Ãè¡ÃШÒ¼èÒ¹ËÅÍ´àÅ×Í´´Ó·ÕèËÒ§¢Í§Ë¹Ù «Ö觼šÒ÷´Åͧ¾ºÇèÒ PGG ÊÒÁÒöÂѺÂÑ駡ÒÃà¨ÃÔ­àµÔºâµ¢Í§à¹×éͧ͡ Å´¡ÒÃáÊ´§ÍÍ¡¢Í§ CSCs áÅÐ EMT ÃÇÁ·Ñ駡ÃеØ鹡ÒÃà¡Ô´¡ÒõÒ¢ͧà«ÅÅìẺÍо;⵫ÔÊä´éÍÂèÒ§ÁÕ»ÃÐÊÔ·¸ÔÀÒ¾â´ÂÊÃØ» PGG áÊ´§ÈÑ¡ÂÀҾ㹡ÒÃÂѺÂÑ駡ÒÃà¨ÃÔ­¢Í§ÁÐàÃç§ÅÓäÊé·Õè´×é͵èÍÂÒ 5-FU ·Ñé§ã¹ÃдѺà«ÅÅìáÅÐÊѵÇì·´Åͧ â´ÂÍÍ¡Ä·¸Ôì¼èÒ¹¡ÒÃÂѺÂÑé§àÊé¹·Ò§ JAK1/JAK3-STAT3 «Ö觪ÕéãËéàË繶֧¤ÇÒÁà»ç¹ä»ä´é㹡ÒþѲ¹Ò PGG à»ç¹ÊÒõéÒ¹ÁÐàÃ秪¹Ô´ãËÁè áÅÐà»ç¹á¹Ç·Ò§·Õè¹èÒʹã¨ÊÓËÃѺ¡ÒÃÈÖ¡ÉÒ·Ò§¤ÅÔ¹Ô¡ã¹Í¹Ò¤µ

Chiang Mai University. Library

Address: CHIANG MAI

Email: cmulibref@cmu.ac.th

Name: Nathupakorn Dechsupa

Role: Advisor

Name: Muhan, Lu

Role: Advisor

Name: Jiraporn Kantapan

Role: Advisor

Created: 2025

Modified: 2568-10-24

Issued: 2025-09-22

ÇÔ·ÂÒ¹Ô¾¹¸ì/Thesis

application/pdf

eng

DegreeName: Doctor of Philosophy

Level: Doctoral Degree

Descipline: Biomedical Science

Grantor: Chiang Mai University

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