Abstract
Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance.
Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway.
Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically.
Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib.
Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.
Keywords: Hcc, dena, sorafenib, dantrolene sodium, ca+2, pi3k.
Graphical Abstract
Current Molecular Pharmacology
Title:Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca+2/PI3K Signaling Pathway
Volume: 14
Author(s): Sherin Zakaria, Abeer Ansary*, Nabil M. Abdel-Hamid and Mamdouh M. El-Shishtawy*
Affiliation:
- Department of Biochemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516,Egypt
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516,Egypt
Keywords: Hcc, dena, sorafenib, dantrolene sodium, ca+2, pi3k.
Abstract:
Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance.
Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway.
Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically.
Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib.
Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.
Export Options
About this article
Cite this article as:
Zakaria Sherin , Ansary Abeer *, Abdel-Hamid M. Nabil and El-Shishtawy M. Mamdouh*, Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca+2/PI3K Signaling Pathway, Current Molecular Pharmacology 2021; 14 (5) . https://dx.doi.org/10.2174/1874467214666210126110627
DOI https://dx.doi.org/10.2174/1874467214666210126110627 |
Print ISSN 1874-4672 |
Publisher Name Bentham Science Publisher |
Online ISSN 1874-4702 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
ABC Transporters: Unvalidated Therapeutic Targets in Cancer and the CNS
Anti-Cancer Agents in Medicinal Chemistry HR MAS MR Spectroscopy in Metabolic Characterization of Cancer
Current Topics in Medicinal Chemistry Himalayan Plants as a Source of Anti-Cancer Agents: A Review
The Natural Products Journal Signaling Transduction Network Mediated by Tumor Suppressor/Susceptibility Genes in NPC
Current Genomics Antineoplastic Activity of an Old Natural Antidiabetic Biguanide on the Human Thyroid Carcinoma Cell Line
Anti-Cancer Agents in Medicinal Chemistry Receptor Mediated Tumor Targeting: An Emerging Approach for Cancer Therapy
Current Drug Delivery Natural Killer Cells Preferentially Target Cancer Stem Cells; Role of Monocytes in Protection Against NK Cell Mediated Lysis of Cancer Stem Cells
Current Drug Delivery Recent Progress in the Development of Natural ent-Kaurane Diterpenoids with Anti-tumor Activity
Mini-Reviews in Medicinal Chemistry Scaffolds for Blocking Protein-Protein Interactions
Current Topics in Medicinal Chemistry Advances in Drug Delivery from Nose to Brain: An Overview
Current Drug Therapy Histone Deacetylase Inhibitors as Potent Modulators of Cellular Contacts
Current Drug Targets Tribbles-Related Protein Family Members as Regulators or Substrates of the Ubiquitin-Proteasome System in Cancer Development
Current Cancer Drug Targets Meet Our Editorial Board Member
Anti-Cancer Agents in Medicinal Chemistry Advances in Colloidal Processing of Rare Earth Particles
Current Smart Materials (Discontinued) MicroRNAs Regulate the Epithelial to Mesenchymal Transition (EMT) in Cancer Progression
MicroRNA Recent Developments of Flavonoids with Various Activities
Current Topics in Medicinal Chemistry Critical Role of Hypoxia Sensor - HIF-1α in VEGF Gene Activation. Implications for Angiogenesis and Tissue Injury Healing
Current Medicinal Chemistry Co-formulation of P-glycoprotein Substrate and Inhibitor in Nanocarriers: An Emerging Strategy for Cancer Chemotherapy
Current Cancer Drug Targets Some Wild-Growing Plant Species from Serbia and Montenegro as the Potential Sources of Drugs
Current Pharmaceutical Design The Apoptosis-Inducing Effects of HIV vpr Recombinant Eukaryotic Expression Vectors with Different Mutation Sites on Transfected Hela Cells
Current HIV Research