Drug Information

Drug (ID: DG00248) and It's Reported Resistant Information

• Name: Isoarnebin 4
• Synonyms: Shikonin; NSC 252844; Shikonin S; Shikonin,(S); Tokyo Violet
• Indication:
  In total 1 Indication(s)
  COVID-19 [ICD-11: 1D92]; Investigative; [1]
• Target: COVID-19 papain-like proteinase (PL-PRO); R1AB_SARS2 (819-2763); [1]
• Formula: C16H16O5
• IsoSMILES: CC(=CC[C@H](C1=CC(=O)C2=C(C=CC(=C2C1=O)O)O)O)C
• InChI: 1S/C16H16O5/c1-8(2)3-4-10(17)9-7-13(20)14-11(18)5-6-12(19)15(14)16(9)21/h3,5-7,10,17-19H,4H2,1-2H3/t10-/m1/s1
• InChIKey: NEZONWMXZKDMKF-SNVBAGLBSA-N
• PubChem CID: 479503
• ChEBI ID: CHEBI:81068
• TTD Drug ID: D0QM4U

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: BAG family molecular chaperone regulator 3 (BAG3) [1]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.31E-08; Fold-change: -2.29E-01; Z-score: -9.50E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-143 enhances the antitumor activity of shikonin by targeting BAG3 and reducing its expression in human glioblastoma stem cell.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-143 [1]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-143 enhances the antitumor activity of shikonin by targeting BAG3 and reducing its expression in human glioblastoma stem cell.

Oral squamous cell carcinoma [ICD-11: 2B6E]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: BCL2 associated X protein (BAX) [2]

• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Activation; hsa04210
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: H357 cells; Oral; Homo sapiens (Human); CVCL_2462
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• Experiment for Molecule Alteration: Reactive oxygen species measurement assay; Mitochondrial membrane potential measurement assay; CD spectroscopy assay; DNA interaction assay; qRT-PCR; Western blot assay
• Experiment for Drug Resistance: Drug release assay; Cell viability assay; Morphological assay; Clonogenic assay; Tumor spheres assay; Annexin V-FITC/PI staining assay; Antimigratory assay
• Mechanism Description: Our study revealed the release time and anticancer potential of Shk on the SCC9 and H357 oral cancer cell lines. We investigated the antiproliferative, antimigratory, cell cycle arresting and apoptosis promoting activity of Shk in oral cancer cells by performing MTT and morphological assay, colony, and tumor sphere formation assay, AO/EtBr and DAPI staining, Annexin V-FITC/PI staining, assay for reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) measurement, comet assay, qRT-PCR, and western blot analysis. We also checked the interaction of DNA and Shk by docking and CD spectroscopy and EtBr displacement assay. As a result, we found that Shk reduced the viability, proliferation, and tumorigenicity of SCC9 and H357 cells in a time and concentration-dependent manner. We obtained half-maximal inhibitory concentration (IC50) at 0.5 uM for SCC9 and 1.25 uM for H357. It promotes apoptosis via overexpressing proapoptotic Bax and caspase 3 via enhancing ROS that leads to MMP depletion and DNA damage and arrests cells at the G2/M & G2/S phase. The antimigratory activity of Shk was performed by analyzing the expression of markers of epithelial-mesenchymal transition like E-cadherin, ZO-1, N-cadherin, and vimentin. These overall results recommended that Shk shows potent anticancer activity against oral cancer cell lines in both in vitro and ex vivo conditions. So, it could be an excellent agent for the treatment of oral cancer.

Key Molecule: Caspase-3 (CASP3) [2]

• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Activation; hsa04210
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: H357 cells; Oral; Homo sapiens (Human); CVCL_2462
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• Experiment for Molecule Alteration: Reactive oxygen species measurement assay; Mitochondrial membrane potential measurement assay; CD spectroscopy assay; DNA interaction assay; qRT-PCR; Western blot assay
• Experiment for Drug Resistance: Drug release assay; Cell viability assay; Morphological assay; Clonogenic assay; Tumor spheres assay; Annexin V-FITC/PI staining assay; Antimigratory assay
• Mechanism Description: Our study revealed the release time and anticancer potential of Shk on the SCC9 and H357 oral cancer cell lines. We investigated the antiproliferative, antimigratory, cell cycle arresting and apoptosis promoting activity of Shk in oral cancer cells by performing MTT and morphological assay, colony, and tumor sphere formation assay, AO/EtBr and DAPI staining, Annexin V-FITC/PI staining, assay for reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) measurement, comet assay, qRT-PCR, and western blot analysis. We also checked the interaction of DNA and Shk by docking and CD spectroscopy and EtBr displacement assay. As a result, we found that Shk reduced the viability, proliferation, and tumorigenicity of SCC9 and H357 cells in a time and concentration-dependent manner. We obtained half-maximal inhibitory concentration (IC50) at 0.5 uM for SCC9 and 1.25 uM for H357. It promotes apoptosis via overexpressing proapoptotic Bax and caspase 3 via enhancing ROS that leads to MMP depletion and DNA damage and arrests cells at the G2/M & G2/S phase. The antimigratory activity of Shk was performed by analyzing the expression of markers of epithelial-mesenchymal transition like E-cadherin, ZO-1, N-cadherin, and vimentin. These overall results recommended that Shk shows potent anticancer activity against oral cancer cell lines in both in vitro and ex vivo conditions. So, it could be an excellent agent for the treatment of oral cancer.

Pancreatic cancer [ICD-11: 2C10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Monocarboxylate transporter 4 (MCT4) [3]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PANC-1-CM-enhanced WI-38 cells; Pancreas; Homo sapiens (Human); CVCL_0579
• In Vitro Model: Primary cancer-associated fibroblasts; Pancreas; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects.

Key Molecule: Monocarboxylate transporter 4 (MCT4) [3]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: WI-38 cells; Fetal lung; Homo sapiens (Human); CVCL_0579
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects.

Key Molecule: Monocarboxylate transporter 4 (MCT4) [3]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: BALB/c mice injected with PANC-1 cells; BALB/c mice injected with PANC-1 cells plus CAFs; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects.

References

• Ref 1: MiR-143 enhances the antitumor activity of shikonin by targeting BAG3 expression in human glioblastoma stem cells. Biochem Biophys Res Commun. 2015 Dec 4-11;468(1-2):105-12. doi: 10.1016/j.bbrc.2015.10.153. Epub 2015 Nov 2.
• Ref 2: Shikonin Stimulates Mitochondria-Mediated Apoptosis by Enhancing Intracellular Reactive Oxygen Species Production and DNA Damage in Oral Cancer Cells. J Cell Biochem. 2025 Jan;126(1):e30671.
• Ref 3: Shikonin reverses cancer-associated fibroblast-induced gemcitabine resistance in pancreatic cancer cells by suppressing monocarboxylate transporter 4-mediated reverse Warburg effect. Phytomedicine. 2024 Jan;123:155214.