Molecule Information

General Information of the Molecule (ID: Mol04094)

• Name: BCL2 associated X protein (BAX) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: BCL2
• Gene ID: 596
• Location: chr18:63123346-63320128[-]
• Sequence:
  MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
  ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLH
  LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEY
  LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK
• Function: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells (PubMed:1508712, PubMed:8183370). Regulates cell death by controlling the mitochondrial membrane permeability (PubMed:11368354). Appears to function in a feedback loop system with caspases (PubMed:11368354). Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1) (PubMed:11368354). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function (PubMed:18570871, PubMed:20889974, PubMed:21358617). May attenuate inflammation by impairing NLRP1- inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). .
• Uniprot ID: BCL2_HUMAN
• Ensembl ID: ENSG00000171791
• HGNC ID: HGNC:990

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; S1148A
• Mechanism Description: Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [3]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Idebenone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diabetic retinopathy [ICD-11: 9B71.0] [4]

• Sensitive Disease: Diabetic retinopathy [ICD-11: 9B71.0]
• Sensitive Drug: Idebenone
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Akt signaling pathway; Regulation; N.A.
• In Vitro Model: RF/6A cells; Chorioretinal; Homo sapiens (Human); CVCL_4552
• In Vivo Model: Diabetic rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Ocular fundus ultrasound testing; Histological assay; Cell proliferation assay
• Mechanism Description: IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.The PI3K/Akt/mTOR signaling pathway acts as the mediator of IDE in alleviating DR.IDE treatment suppressed the activation of the PI3K/Akt/mTOR signaling pathway, and PI3K signaling repressed the protective role of IDE in DR, explaining the IDE-suppressed autophagy in DR.

Irinotecan

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [ICD-11: 2B90.1] [5]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Irinotecan
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Immunoblotting assay; qRT-PCR; Immunofluorescence staining assay; Reporter Gene assay; RNA sequencing assay
• Experiment for Drug Resistance: Cell cytotoxicity assay; Tumorigenicity assay
• Mechanism Description: Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies.

Investigative Drug(s) 1 drug(s) in total

Isoarnebin 4

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Oral squamous cell carcinoma [ICD-11: 2B6E.0] [6]

• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Sensitive Drug: Isoarnebin 4
• 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.

References

• Ref 1: Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. Genes (Basel). 2024 May 20;15(5):648.
• Ref 2: MiR-34c-5p Inhibition Affects Bax/Bcl2 Expression and Reverses Bortezomib Resistance in Multiple Myeloma Cells. Indian J Hematol Blood Transfus. 2024 Oct;40(4):596-603.
• Ref 3: Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a TP53- and BAX-Dependent Manner. Clin Cancer Res. 2021 Sep 1;27(17):4910-4922.
• Ref 4: Idebenone Attenuates Diabetic Retinopathy by Modulating Autophagy Via Targeting Akt Signaling. Curr Med Chem. 2024 Nov 1.
• Ref 5: Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer. Cancers (Basel). 2024 Oct 15;16(20):3491.
• Ref 6: 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.