Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer

Forouzan Amerizadeh; Farzad Rahmani; Mina Maftooh; Seyedeh-Najibeh Nasiri; Seyed Mahdi Hassanian; Elisa Giovannetti; Reyhaneh Moradi-Marjaneh; Reihaneh Sabbaghzadeh; Soodabeh Shahidsales; Mona Joudi-Mashhad; Majid Ghayour-Mobarhan; Gordon A. Ferns; Majid Khazaei; Amir Avan

doi:10.1016/j.tice.2022.101853

Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer

Forouzan Amerizadeh
, Farzad Rahmani
, Mina Maftooh
, Seyedeh-Najibeh Nasiri
, Seyed Mahdi Hassanian
, Elisa Giovannetti
, Reyhaneh Moradi-Marjaneh
, Reihaneh Sabbaghzadeh
, Soodabeh Shahidsales
, Mona Joudi-Mashhad
, Majid Ghayour-Mobarhan
, Gordon A. Ferns
, Majid Khazaei^*
, Amir Avan^*

^*Corresponding author for this work

Mashhad University of Medical Sciences
Amsterdam UMC
Cancer Pharmacology Lab, Pisa, Italy
Hakim Sabzevari University
Brighton and Sussex Medical School

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. Methods: The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. Results: PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. Conclusions: Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer.

Original language	English
Article number	101853
Journal	Tissue and Cell
Volume	77
DOIs	https://doi.org/10.1016/j.tice.2022.101853
Publication status	Published - 1 Aug 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

5-FU combination
Anti-tumor effect
Colorectal cancer
PNU-74654
Wnt pathway

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10.1016/j.tice.2022.101853

Inhibition-of-the-wntb-catenin-pathway-using-pnu-74654-reduces-tumor-growth-in-in-vitro-and-in-vivo-models-of-colorecta.pdfFinal published version, 6.85 MBLicence: Taverne

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Amerizadeh, F., Rahmani, F., Maftooh, M., Nasiri, S.-N., Hassanian, S. M., Giovannetti, E., Moradi-Marjaneh, R., Sabbaghzadeh, R., Shahidsales, S., Joudi-Mashhad, M., Ghayour-Mobarhan, M., Ferns, G. A., Khazaei, M., & Avan, A. (2022). Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer. Tissue and Cell, 77, Article 101853. https://doi.org/10.1016/j.tice.2022.101853

@article{0f550ef7070f4d6cbd9a4f6497401799,

title = "Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer",

abstract = "Background: Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. Methods: The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. Results: PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. Conclusions: Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer.",

keywords = "5-FU combination, Anti-tumor effect, Colorectal cancer, PNU-74654, Wnt pathway",

author = "Forouzan Amerizadeh and Farzad Rahmani and Mina Maftooh and Seyedeh-Najibeh Nasiri and Hassanian, \{Seyed Mahdi\} and Elisa Giovannetti and Reyhaneh Moradi-Marjaneh and Reihaneh Sabbaghzadeh and Soodabeh Shahidsales and Mona Joudi-Mashhad and Majid Ghayour-Mobarhan and Ferns, \{Gordon A.\} and Majid Khazaei and Amir Avan",

note = "Funding Information: This research was partly supported by grants awarded by the Mashhad University of Medical Sciences , grant No. 960692 (Amir Avan). Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = aug,

day = "1",

doi = "10.1016/j.tice.2022.101853",

language = "English",

volume = "77",

journal = "Tissue and Cell",

issn = "0040-8166",

publisher = "Elsevier Ltd",

}

Amerizadeh, F, Rahmani, F, Maftooh, M, Nasiri, S-N, Hassanian, SM, Giovannetti, E, Moradi-Marjaneh, R, Sabbaghzadeh, R, Shahidsales, S, Joudi-Mashhad, M, Ghayour-Mobarhan, M, Ferns, GA, Khazaei, M & Avan, A 2022, 'Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer', Tissue and Cell, vol. 77, 101853. https://doi.org/10.1016/j.tice.2022.101853

TY - JOUR

T1 - Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer

AU - Amerizadeh, Forouzan

AU - Rahmani, Farzad

AU - Maftooh, Mina

AU - Nasiri, Seyedeh-Najibeh

AU - Hassanian, Seyed Mahdi

AU - Giovannetti, Elisa

AU - Moradi-Marjaneh, Reyhaneh

AU - Sabbaghzadeh, Reihaneh

AU - Shahidsales, Soodabeh

AU - Joudi-Mashhad, Mona

AU - Ghayour-Mobarhan, Majid

AU - Ferns, Gordon A.

AU - Khazaei, Majid

AU - Avan, Amir

PY - 2022/8/1

Y1 - 2022/8/1

N2 - Background: Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. Methods: The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. Results: PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. Conclusions: Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer.

AB - Background: Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. Methods: The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. Results: PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. Conclusions: Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer.

KW - 5-FU combination

KW - Anti-tumor effect

KW - Colorectal cancer

KW - PNU-74654

KW - Wnt pathway

UR - https://www.scopus.com/pages/publications/85133482487

U2 - 10.1016/j.tice.2022.101853

DO - 10.1016/j.tice.2022.101853

M3 - Article

C2 - 35803035

SN - 0040-8166

VL - 77

JO - Tissue and Cell

JF - Tissue and Cell

M1 - 101853

ER -

Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer

Abstract

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Keywords

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