Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades
Abstract
1. Introduction
2. Results
2.1. Screening of an FDA-Approved Drug Library to Identify Effective Compounds of Inducing Cell Necroptosis
2.2. Menadione Exerted Strong Anti-Tumor Effects on Colorectal Cancer Cells
2.3. Menadione Induced Not Only Necroptosis, but Also Apoptosis and Autophagy in Colorectal Cancer Cells
2.4. The Anti-Tumor Effect Induced by Menadione in Colorectal Cancer Cells Was Mediated Through MAPK8
2.5. Validation of Programmed Cell Death and Upregulation of MAPK8 Cascades Induced by Menadione in Colorectal Cancer Cells
2.6. Drug Targets of Menadione and Role of MAPK8 in CRC
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Drug Treatment and Cell Viability Assay
4.3. mRNA Isolation and Quantitative PCR
4.4. PCR Array and Data Processing
4.5. Bioinformatics Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CRC | Colorectal cancer |
PCD | Programmed cell death |
TNF-α | Tumor necrosis factor alpha |
TSZ | TNF-α, Smac mimetics and Z-VAD-FMK |
DEG | Differentially expressed gene |
GSEA | Gene set enrichment analysis |
PPI | Protein–protein interaction |
GO | Gene ontology |
KEGG | Kyoto encyclopedia of genes and genomes |
TTD | Therapeutic target database |
TNFR1 | Tumor necrosis factor receptor 1 |
NF-κB | Nuclear factor kappa B |
RIA | RIPK1-independent apoptosis |
RDA | RIPK1-dependent apoptosis |
TRADD | TNFR1-associated death domain protein |
FADD | Fas-associated via death domain |
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Classification | Drugs |
---|---|
Psychotropic drugs | Vortioxetine HBr |
Antineoplastic drugs | Menadione, Bosutinib, Crizotinib, Vandetanib, Mesylate |
Bacteriostatic drugs | Crystal Violet |
Cardiovascular drugs | Dronedarone hydrochloride |
Immunomodulatory drugs | Fingolimodhydrochloride |
Endocrine regulating drugs | Bazedoxifene acetate |
Other | Disulfira, Evans blue |
Menadione-3μM | Menadione-8μM | TSZ | ||||||
---|---|---|---|---|---|---|---|---|
Gene Symbol | Change | Log2FC | Gene Symbol | Change | Log2FC | Gene Symbol | Change | Log2FC |
CASP1 | up | 17.39877 | BCL2L1 | up | 9.977538 | CASP9 | up | 11.03449 |
ATP6V1G2 | up | 12.31594 | ULK1 | up | 8.808996 | CD40LG | up | 10.80574 |
CD40 | up | 10.82597 | DEFB1 | up | 8.258613 | GADD45A | up | 10.51166 |
DPYSL4 | up | 8.68331 | BCL2L11 | up | 8.228723 | BCL2L11 | up | 8.151372 |
OR10J3 | up | 8.073124 | C1orf159 | up | 5.281698 | TRAF2 | up | 7.866846 |
GADD45A | up | 7.68622 | CFLAR | up | 5.159871 | C1orf159 | up | 7.289466 |
C1orf159 | up | 5.831624 | GADD45A | up | 4.55888 | GRB2 | up | 6.88594 |
BCL2L11 | up | 4.359662 | ATG3 | up | 4.040016 | CASP1 | up | 5.93121 |
CASP6 | up | 3.908813 | PARP2 | up | 3.966246 | PARP2 | up | 5.601994 |
SQSTM1 | up | 3.707083 | ATG7 | up | 3.331992 | BMF | up | 5.39163 |
CFLAR | up | 3.484138 | CASP1 | up | 3.249445 | XIAP | up | 5.146085 |
MAPK8 | up | 3.117695 | MAPK8 | up | 3.228049 | BCL2L1 | up | 4.340562 |
TRAF2 | up | 3.097611 | EIF5B | up | 3.181103 | TNF | up | 4.008092 |
CASP3 | up | 2.563158 | DFFA | up | 2.584963 | ABL1 | up | 3.989139 |
DFFA | up | 2.395063 | SQSTM1 | up | 2.313246 | GAA | up | 3.280956 |
ATG7 | up | 2.286881 | ACTB | up | 1.526069 | MCL1 | up | 3.144046 |
MCL1 | up | 2.247928 | XIAP | down | −1.23879 | CFLAR | up | 2.536053 |
ATG3 | up | 2.238787 | PVR | down | −2.04264 | BECN1 | up | 2.485427 |
BCL2 | up | 1.967169 | RAB25 | down | −2.16993 | DENND4A | up | 2.169925 |
MAG | up | 1.891419 | PIK3C3 | down | −3.46597 | CASP6 | up | 1.831877 |
GAA | up | 1.807355 | ABL1 | down | −4.71644 | EIF5B | up | 1.495695 |
CD40LG | up | 1.752749 | PARP1 | down | −5.40122 | PIK3C3 | up | 1.344828 |
BECN1 | up | 1.589763 | ATG16L1 | down | −6.36107 | CTSB | down | −2.0321 |
DEFB1 | up | 1.111031 | GALNT5 | down | −7.18378 | ULK1 | down | −2.83188 |
XIAP | down | −2.41414 | SYCP2 | down | −7.31442 | SPATA2 | down | −3.06178 |
RAB25 | down | −2.69822 | SPATA2 | down | −10.957 | ATP6V1G2 | down | −3.64962 |
PIK3C3 | down | −2.79286 | IGF1 | down | −11.894 | BCL2 | down | −3.97728 |
FAS | down | −3.4957 | COMMD4 | down | −5.99186 | |||
TXNL4B | down | −4.89579 | SYCP2 | down | −6.06953 | |||
FOXI1 | down | −4.90593 | ATG16L1 | down | −6.34837 | |||
ATG16L1 | down | −5.17632 | GALNT5 | down | −7.78973 | |||
ABL1 | down | −5.2211 | ||||||
BMF | down | −6.10476 | ||||||
PARP1 | down | −6.11582 | ||||||
APP | down | −6.85723 | ||||||
AKT1 | down | −6.90857 | ||||||
COMMD4 | down | −8.98504 | ||||||
GALNT5 | down | −11.4963 |
Pathway | Genes |
---|---|
Necroptosis | PARP1; poly(ADP-ribose) polymerase 1 |
XIAP; X-linked inhibitor of apoptosis | |
FAS; Fas cell surface death receptor | |
MAPK8; mitogen-activated protein kinase 8 | |
BCL2; BCL2 apoptosis regulator | |
TRAF2; TNF receptor associated factor 2 | |
CASP1; caspase 1 | |
CFLAR; CASP8 and FADD like apoptosis regulator | |
SQSTM1; sequestosome 1 | |
SPATA2; spermatogenesis associated 2 | |
Apoptosis | BCL2L11; BCL2 like 11 |
PARP2; poly(ADP-ribose) polymerase 2 | |
PARP1; poly(ADP-ribose) polymerase 1 | |
GADD45A; growth arrest and DNA damage inducible alpha | |
DFFA; DNA fragmentation factor subunit alpha | |
AKT1; AKT serine/threonine kinase 1 | |
XIAP; X-linked inhibitor of apoptosis | |
FAS; Fas cell surface death receptor | |
MCL1; MCL1 apoptosis regulator, BCL2 family member | |
MAPK8; mitogen-activated protein kinase 8 | |
BCL2; BCL2 apoptosis regulator | |
BCL2L1; BCL2 like 1 | |
ACTB; actin beta | |
TRAF2; TNF receptor associated factor 2 | |
CASP3; caspase 3 | |
CASP6; caspase 6 | |
CFLAR; CASP8 and FADD like apoptosis regulator | |
Autophagy | ATG7; autophagy related 7 |
AKT1; AKT serine/threonine kinase 1 | |
PIK3C3; phosphatidylinositol 3-kinase catalytic subunit type 3 | |
ATG16L1; autophagy related 16 like 1 | |
MAPK8; mitogen-activated protein kinase 8 | |
BCL2; BCL2 apoptosis regulator | |
BCL2L1; BCL2 like 1 | |
ATG3; autophagy related 3 | |
ULK1; unc-51 like autophagy activating kinase 1 | |
BECN1; beclin 1 | |
CFLAR; CASP8 and FADD like apoptosis regulator | |
SQSTM1; sequestosome 1 |
No. | Pharma Model | No. Feature | Fit | Norm Fit | Symbol |
---|---|---|---|---|---|
1 | 1ggt_A_cavity_2 | 5 | 2.48 | 0.496 | F13A1 |
2 | 1x65_A_cavity_1 | 6 | 2.973 | 0.4954 | CSDE1 |
3 | 1mj4_A_cavity_1 | 7 | 2.811 | 0.4016 | SUOX |
4 | 2f8x_C_cavity_3 | 7 | 2.687 | 0.3838 | NOTCH1 |
5 | 2bug_A_cavity_1 | 8 | 2.881 | 0.3601 | HSP90AA1 |
6 | 2p0k_A_cavity_2 | 9 | 2.684 | 0.2982 | SCMH1 |
7 | 1o7k_C_cavity_1 | 10 | 2.652 | 0.2652 | NCF1 |
8 | 1i0e_B_cavity_2 | 11 | 2.79 | 0.2536 | CKM |
9 | 1rc1_A_cavity_1 | 12 | 2.908 | 0.2423 | GART |
10 | 1ljr_A_cavity_1 | 12 | 2.868 | 0.239 | GSTT2B |
11 | 2pvs_B_cavity_2 | 12 | 2.355 | 0.1962 | PNLIPRP2 |
12 | 3bpj_D_cavity_1 | 19 | 2.755 | 0.145 | EIF3J |
13 | 2vwi_B_cavity_1 | 26 | 2.816 | 0.1083 | OXSR1 |
14 | 1pc2_A_cavity_1 | 26 | 2.795 | 0.1075 | FIS1 |
15 | 1pu5_C_cavity_2 | 31 | 2.871 | 0.09262 | GM2A |
16 | 1us1_B_cavity_1 | 40 | 2.817 | 0.07042 | AOC3 |
17 | 2k21_A_cavity_1 | 50 | 2.653 | 0.05306 | KCNE1 |
18 | 2o36_A_cavity_2 | 70 | 2.919 | 0.04171 | THOP1 |
Databases | Drug Targets |
---|---|
Pharmmapper | F13A1, CSDE1, SUOX, NOTCH1, HSP90AA1, SCMH1, NCF1, CKM, GART, GSTT2B, PNLIPRP2, EIF3J, OXSR1, FIS1, GM2A, AOC3, KCNE1, THOP1 |
Drugbank | GGCX, VKORC1, VKORC1L1, F2, F7, F9, F10, PROC, PROS1, PROZ, NQO2, NQO1, BGLAP, |
TTD | AOX1, V1R |
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Cao, L.; Song, W.; Sun, J.; Ge, Y.; Mu, W.; Li, L. Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades. Pharmaceuticals 2025, 18, 1145. https://doi.org/10.3390/ph18081145
Cao L, Song W, Sun J, Ge Y, Mu W, Li L. Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades. Pharmaceuticals. 2025; 18(8):1145. https://doi.org/10.3390/ph18081145
Chicago/Turabian StyleCao, Liyuan, Weiwei Song, Jinli Sun, Yang Ge, Wei Mu, and Lei Li. 2025. "Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades" Pharmaceuticals 18, no. 8: 1145. https://doi.org/10.3390/ph18081145
APA StyleCao, L., Song, W., Sun, J., Ge, Y., Mu, W., & Li, L. (2025). Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades. Pharmaceuticals, 18(8), 1145. https://doi.org/10.3390/ph18081145