Disease Information

General Information of the Disease (ID: DIS00567)

• Name: Unspecified malignant neoplasms of unspecified sites
• ICD: ICD-11: 2D4Z

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Calcium/manganese antiporter SLC30A10 (SLC30A10) [3]

• Resistant Disease: cancer [ICD-11: 2D4Z]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of?SLC30A10?resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of?SLC30A3?resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Probable proton-coupled zinc antiporter SLC30A3 (SLC30A3) [3]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of?SLC30A10?resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of?SLC30A3?resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: P-glycoprotein (ABCB1) [4]

• Resistant Disease: cancer [ICD-11: 2D4Z]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; T790M; C797S
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HBL-100/DOX cells; epithelial cell; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Microculture tetrazolium assay
• Mechanism Description: The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression.

Stavudine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) [5]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: Stavudine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Interferon type I signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: FVB/N-TgN 202Mul mice model; Mus musculus
• Experiment for Molecule Alteration: Global transcriptome assay
• Experiment for Drug Resistance: L1 retrotransposition assay
• Mechanism Description: the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-kappaB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-kappaB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population.

Investigative Drug(s) 3 drug(s) in total

3-Deazaneplanocin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [2]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: 3-Deazaneplanocin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment.

Key Molecule: Histone H3 lysine 27 trimethylation (H3K27me3) [2]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: 3-Deazaneplanocin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment.

DB2Py

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: P-glycoprotein (ABCB1) [4]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: DB2Py
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HBL-100/DOX cells; epithelial cell; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Microculture tetrazolium assay
• Mechanism Description: The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression.

MB2Py

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: P-glycoprotein (ABCB1) [4]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: MB2Py
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HBL-100/DOX cells; epithelial cell; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Microculture tetrazolium assay
• Mechanism Description: The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression.

References

• Ref 1: Foretinib, a c-MET receptor tyrosine kinase inhibitor, tackles multidrug resistance in cancer cells by inhibiting ABCB1 and ABCG2 transporters. Toxicol Appl Pharmacol. 2024 Mar;484:116866.
• Ref 2: 3-deazaneplanocin A, a histone methyltransferase inhibitor, improved the chemoresistance induced under hypoxia in melanoma cells. Biochem Biophys Res Commun. 2023 Oct 15;677:26-30.
• Ref 3: Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells. Int J Mol Sci. 2024 Nov 9;25(22):12049.
• Ref 4: Dimeric Bis-Benzimidazole-Pyrroles DB2Py(n) - AT-Site-Specific Ligands: Synthesis, Physicochemical Analysis, and Biological Activity. Acta Naturae. 2024 Jan-Mar;16(1):86-100.
• Ref 5: Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2213146119.