Drug Information

Drug (ID: DG01243) and It's Reported Resistant Information

• Name: Lobaplatin
• Synonyms: 131374-93-1; [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+); Lobaplatine; Lobaplatino; Lobaplatinum; Lobaplatin [INN]; Lobaplatine [INN-French]; Lobaplatinum [INN-Latin]; Lobaplatino [INN-Spanish]; NSC619413; NSC 741422; NSC-619413; 2-(Aminomethyl)cyclobutyl]methanamine 2-hydroxypropanoic acid platinum salt; cis-((trans-1,2-Cyclobutandimethylamine)-(s)-2-oxidopropanoato-platinum(II)); cis-(trans-1,2-Cyclobutanebis(methylamine))((S)-lactato-O(sup 1),O(sup 1))platinum; Platinum, (1,2-cyclobutanedimethanamine-N,N')(2-hydroxypropanoato(2-)-O1,O2)-, (SP-4-3-(S),(trans))-; Platinum, (rel-(1R,2R)-1,2-cyclobutanedimethanamine-kappaN,kappaN')((2S)-2-(hydroxy-kappa-O)propanoato(2-)-kappaO)-, (SP-4-3)-; Platinum,2-cyclobutanedimethanamine-N,N') [2-hydroxypropanoato(2-)-O(1),O(2)]-, (SP-4-3)
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Osteosarcoma [ICD-11: 2B51]; [3]
• Formula: C9H18N2O3Pt+2
• IsoSMILES: CC(C(=O)[O-])[O-].C1CC(C1CN)CN.[Pt+4]
• InChI: 1S/C6H14N2.C3H5O3.Pt/c7-3-5-1-2-6(5)4-8;1-2(4)3(5)6;/h5-6H,1-4,7-8H2;2H,1H3,(H,5,6);/q;-1;+4/p-1
• InChIKey: XSMVECZRZBFTIZ-UHFFFAOYSA-M
• PubChem CID: 24202037
• TTD Drug ID: D0S4QZ

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Osteosarcoma [ICD-11: 2B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Far upstream element-binding protein 1 (FUBP1) [3]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Arachidonic acid metabolic signaling pathway; Regulation; N.A.
• In Vitro Model: MG-63 cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: SOSP-9607 cells; Bones; Homo sapiens (Human); CVCL_4V80
• In Vivo Model: Female nude mice model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Western blot assay; H&E assay; Immunohistochemistry; Immunofluorescence staining assay; RNA FISH assay; RNA sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Colony formation assay; Cytotoxicity assay
• Mechanism Description: The expression of far upstream element-binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin-induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation-seq and RNA-seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Far upstream element-binding protein 1 (FUBP1) [1]

• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: SH-1-V6 cells; Esophagus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: FUBP1 knockdown conferred lobaplatin sensitivity of osteosarcoma SaOS-2 Cells.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Histone acetyltransferase p300 (EP300) [2]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vivo Model: Female nude mice model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Western blot assay; Immunofluorescence staining assay; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: CCK8 cell cytotoxicity assay; Cell proliferation assay; Cell invasion assay; TUNEL analysis; Sphere-forming assay; Colony formation assay; Xenograft assay
• Mechanism Description: Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

Key Molecule: Cysteine-rich secretory protein 3 (CRISP3) [2]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vivo Model: Female nude mice model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Western blot assay; Immunofluorescence staining assay; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: CCK8 cell cytotoxicity assay; Cell proliferation assay; Cell invasion assay; TUNEL analysis; Sphere-forming assay; Colony formation assay; Xenograft assay
• Mechanism Description: Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

References

• Ref 1: Protein and Signaling Pathway Responses to rhIL-6 Intervention Before Lobaplatin Treatment in Osteosarcoma Cells .Front Oncol. 2021 Mar 9;11:602712. doi: 10.3389/fonc.2021.602712. eCollection 2021. 10.3389/fonc.2021.602712
• Ref 2: EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer. Hum Cell. 2024 Sep;37(5):1475-1488.
• Ref 3: Far upstream element-binding protein 1 confers lobaplatin resistance by transcriptionally activating PTGES and facilitating the arachidonic acid metabolic pathway in osteosarcoma. MedComm (2020). 2023 May 9;4(3):e257.