Pectasol-C Modified Citrus Pectin targets Galectin-3-induced STAT3 activation and synergize paclitaxel cytotoxic effect on ovarian cancer spheroids.

Abstract

Here we sought to determine the relationship between STAT3 activity and Galectin-3 (Gal-3) and to investigate the cytotoxic effect of PectaSol-C Modified Citrus Pectin (Pect-MCP) as a specific competitive inhibitor of Galectin-3 (Gal-3) in combination with Paclitaxel (PTX) to kill the ovarian cancer cell SKOV-3 multicellular tumor spheroid (MCTS). To this order, SKOV-3 cells in 2D and 3D cultures were treated with exogenous Gal-3 for the assessment of STAT3 activity. Two-way ANOVA main effect and IC50 of each drug Paclitaxel (PTX) and Pect-MCP or in combination were obtained from MTT assay results. The phosphorylated STAT3 levels, migration, invasion, integrin mRNA and p-AKTser473 levels were assessed in the absence or presence of each drug alone or in combination. Gal-3 expression levels were assessed in human serous ovarian cancer (SOC) specimens and its correlation with different integrin mRNA levels was further assessed. Our results showed that Gal-3 expression level was significantly increased in MCTS compared to monolayer SKOV-3 cells which triggered STAT3 phosphorylation. Moreover, Pect-MCP synergized with PTX to kill SKOV3 MCTS through abrogation of STAT3 activity and reduced expression of its downstream target HIF-1α, reduced integrin mRNA levels, and subsequently decreased AKT activity. There were higher expression levels of Gal-3 in human high-grade SOC specimens compared to the normal ovary and borderline SOC which positively and significantly correlated with α5, β2 and β6 integrin mRNA levels. Together, these results revealed for the first time that Pect-MCP could be considered as a potential drug to enhance the PTX effect on ovarian cancer cells MCTS through inhibition of STAT3 activity.

• Authors: Ghamartaj Hossein, Sina Halvaei, Yassaman Heidarian, Zeinab Dehghani-Ghobadi, Mina Hassani, Homa Hosseini, Nima Naderi, Shahrzad Sheikh Hassani
• Journal: Cancer medicine (Cancer Med) Vol. 8 Issue 9 Pg. 4315-4329 (08 2019) ISSN: 2045-7634 [Electronic] United States
• PMID: 31197964 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Blood Proteins
• Galectin 3
• Galectins
• Integrins
• LGALS3 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• citrus pectin
• Pectins
• Paclitaxel

Topics

• Blood Proteins
• Cell Culture Techniques
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cystadenocarcinoma, Serous (drug therapy, genetics, metabolism, pathology)
• Drug Synergism
• Female
• Galectin 3 (metabolism)
• Galectins
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Integrins (genetics)
• Neoplasm Grading
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Paclitaxel (pharmacology)
• Pectins (pharmacology)
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Spheroids, Cellular (cytology, drug effects)
• Tumor Cells, Cultured