(Curcumin+sildenafil) enhances the efficacy of 5FU and anti‐PD1 therapies in vivo

2020/01/27 by Paul Dent, Laurence Booth, Jane L. Roberts +2 · 17 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Adenosine and Purinergic Signaling #Biology #Biotechnology #Cancer research #Chemistry #Curcumin #Curcumin's Biomedical Applications #Endoplasmic Reticulum Stress and Disease #In vivo #Internal medicine #Medicine #Oncology #Pharmacology #Sildenafil

paper · doi:10.1002/jcp.29580

openalex publication_date 2020/01/27 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

We have extended our analyses of (curcumin+sildenafil) biology. The drug combination caused vascularization and degradation of mutant K-RAS that correlated with reduced phosphorylation of ERK1/2, AKT T308, mTORC1, mTORC2, ULK1 S757, STAT3, STAT5, and NFκB and increased phosphorylation of eIF2α, ATM, AMPKα, ULK1 S317; all concomitant with elevated ATG13 S318 phosphorylation and autophagosome formation. Prior studies with drug combinations utilizing sildenafil have delineated an ATM-AMPK-ULK1 S317 pathway and an AKT-mTOR-ULK1 S757 pathway as modules which control ATG S318 phosphorylation and autophagosome formation. The knockdown of PKG reduced cell killing as well as reducing drug-enhanced phosphorylation of ATM, AMPKα, and ATG13. In the absence of PKG, no significant increase in ULK1 S317 phosphorylation was observed. In a Beclin1-dependent fashion, the drug combination reduced the expression of multiple histone deacetylase (HDAC) proteins, including HDAC2 and HDAC3. Molecular knockdown of HDAC2, HDAC3, and especially (HDAC2+HDAC3) significantly reduced the expression of PD-L1 and elevated expression of Class I human major histocompatibility complex. In vivo, (curcumin+sildenafil) enhanced the efficacy of 5-flurouracil against CT26 colorectal tumors. Prior exposure of established CT26 tumors to (curcumin+sildenafil) significantly enhanced the efficacy of a subsequently administered anti-PD-1 antibody. Collectively our data argue that (curcumin+sildenafil) has the potential in several settings to be an efficacious neoadjuvant therapy for colon cancer.

Cited by

• The Role of Histone Acetylation and the Microbiome in Phytochemical Efficacy for Cardiovascular Diseases. [europepmc]
• GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling. [europepmc]
• New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil. [europepmc]
• The interplay between diet, gut microbes, and host epigenetics in health and disease. [europepmc]
• Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era. [europepmc]
• Curcumin in Osteosarcoma Therapy: Combining With Immunotherapy, Chemotherapeutics, Bone Tissue Engineering Materials and Potential Synergism With Photodynamic Therapy. [europepmc]
• The Potential Role of Sildenafil in Cancer Management through EPR Augmentation. [europepmc]
• Autophagy controls programmed death-ligand 1 expression on cancer cells (Review). [europepmc]
• Dietary Polyphenols: Promising Adjuvants for Colorectal Cancer Therapies. [europepmc]
• Can Natural Products be Used to Overcome the Limitations of Colorectal Cancer Immunotherapy? [europepmc]
• GZ17-6.02 kills prostate cancer cells in vitro and in vivo . [europepmc]
• Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis. [europepmc]
• GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells. [europepmc]
• GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells. [europepmc]
• Polyphenolic Compounds: Orchestrating Intestinal Microbiota Harmony during Aging. [europepmc]
• Repurposing of phosphodiesterase-5 inhibitor sildenafil as a therapeutic agent to prevent gastric cancer growth through suppressing c-MYC stability for IL-6 transcription. [europepmc]
• Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer. [europepmc]

Related

• Curcumin as an Anti-Cancer Agent: Review of the Gap Between Basic and Clinical Applications
• Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases
• Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2
• Exploring the Mechanism of Curcumin in the Treatment of Gastric Cancer based on Network Pharmacology, Molecular Dynamics Simulation, and In Vitro Experimental Verification
• Curcumin, an active component of turmeric (Curcuma longa), and its effects on health