Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study
Abstract
1. Introduction
2. Results
2.1. Effects of Treatments on Tumor Growth
2.2. Histological and Immunofluorescence Analysis of Tumor Tissues
2.2.1. Regulation of MITF in Response to Treatments
2.2.2. Expression and Activation of Key Oncogenic Signaling Proteins
2.3. Transcriptomic Analysis via RNA-Seq
2.3.1. Differential Gene Expression Analysis
2.3.2. Clustered Gene Expression Patterns
2.3.3. Functional Enrichment and Pathway Analysis
2.4. In Silico Analysis of Drug–Target Interactions
- For B-RAF, PTX showed predicted interactions with Lys483 and Asp594, both essential residues within the ATP binding site [17], suggesting potential interference with kinase activity;
- For mTOR, PTX docked at residues Gln1901, His2410, and Asp2412, located near the kinase catalytic site [18];
- For PIK3CA (PI3K catalytic subunit alpha), PTX interacted with residues such as His670 and Arg818, known to participate in PI3K activation [19];
- For HIF1A, NCTD showed the strongest binding energy (−7.8 kcal/mol), with interactions at residues Arg383 and His374, both involved in transcriptional regulation under hypoxic conditions [20].
3. Discussion
Limitations
4. Methods and Materials
4.1. Cell Culture
4.2. Establishment of the Murine Melanoma Model
4.3. Pharmacological Treatments
4.4. Total RNA Extraction and cDNA Library Preparation
4.5. RNA Sequencing and Data Acquisition
4.6. RNA-Seq Data Analysis Pipeline
4.7. Tumor Tissue Immunofluorescence
4.8. Molecular Docking Studies
4.9. Statical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CDH1 | E-cadherin |
FZD8 | Frizzled-8 receptor |
TGF-β1 | Transforming growth factor beta 1 |
CTNND1 | p120-catenin |
LFA-1 | CD11a/CD18 integrin complex = ITGAL/ITGB2 |
CXCL12γ | C-X-C motif chemokine ligand 12, gamma subunit |
Claudin-2 | CLDN2 |
PIK3CA | PI3K catalytic subunit p110α |
AKT1 | AKT serine/threonine protein kinase 1 |
mTOR | Mechanistic target of rapamycin |
ERK2 | MAPK1 protein |
CD117 | KIT receptor |
KITLG | Stem Cell Factor (KIT ligand) |
KDM5B | Histone demethylase |
MITF | Microphthalmia-associated TF |
B-RAF | B-Raf proto-oncogene serine/threonine-protein kinase |
ERBB2 | HER2 receptor |
HIF1A | Hypoxia-inducible factor 1-alpha |
VEGF-A | Vascular endothelial growth factor A |
EGF | Epidermal growth factor |
TWIST1 | Twist-related protein 1 |
PTGS2 | Cyclooxygenase-2 |
PDPK1 | 3-phosphoinositide-dependent protein kinase-1 |
NF-κB | NF-κB complex |
GO | Gene Ontology |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
Reactome | Reactome Pathway Database |
GSEA | Gene Set Enrichment Analysis |
SD | Standard deviation |
D | Day (D6, Day 6) |
ΔG | Binding free energy |
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Protein | PDB ID | Ligand | Binding Energy (ΔG, kcal/mol) | Binding Site/Residues |
---|---|---|---|---|
Epithelial–Mesenchymal Transition (EMT) | ||||
CDH1 | 3Q2V | NCTD | −4.76 | Tyr175, Asp168. Leu167 |
PTX | −4.96 | Met193, Glu190, His180 | ||
LIM domain-binding protein 1 | 6PTL | NCTD | −5.47 | Gln125, Gly144, Glu143 |
PTX | −5.23 | Ile165, Phe72, Ile70, Met128, Tyr91, Ile95, Ser94, His132 | ||
FZD8 | 1IJY | NCTD | −6.16 | Gly113, Val114, Cys115, Val109, Pro108, Lys77 |
PTX | −6.44 | Ser78, Cys115, Gly113, Lys77, Pro108, Lys74, Val109 | ||
TGF-β1 | 1KLC | NCTD | −4.79 | Arg25, Lys37, Phe24, His34 |
PTX | −5.00 | Arg25, Phe24, His34 | ||
CTNND1 | 3L6X | NCTD | −5.52 | Asp510, Arg383 |
PTX | −5.20 | Lue620, Glu521, Arg326, Arg329, Val514, Asn517 | ||
LFA-1 | 3F74 | NCTD | −4.91 | Gly262, Leu289, Ile288, Asp290 |
PTX | −5.06 | Thr164, Tyr166, Ser165, Thr231, Gly128 | ||
CXCL12γ | 6EHZ | NCTD | −5.11 | Arg12, Cys50, Val49 |
PTX | −5.06 | Arg12, Cys50, Arg47, Val39, Gln46 | ||
Claudin-2 | 4YYX | NCTD | −6.18 | Ile38, Ile36, Gly35, Phe34, Leu95, Arg96 |
PTX | −6.47 | Asn72, Arg74, Glu51, His46, Gly40, Val55 | ||
Cell Proliferation | ||||
PIK3CA | 4A55 | NCTD | −5.72 | Gln1033, Leu1036, Glu1037, Thr1040 |
PTX | −6.50 | His670, Arg662, Asn170, Arg818, Cys838, Leu839 | ||
AKT1 | 3O96 | NCTD | −5.99 | Leu360, Tyr340, Arg367, Arg346, Leu347, Pro358, Phe349, Tyr350 |
PTX | −6.10 | Leu52, Pro51, Asp325, Gly327 | ||
mTOR | 6BCX | NCTD | −6.60 | His1398, Trp2313, Trp2304, Ala2386 |
PTX | −6.88 | Gln1901, His2410, Asp2412 | ||
ERK2 | 6GJD | NCTD | −6.60 | Val39, Lys54, Thr105 |
PTX | −6.70 | Leu156, Lys54, Ala52, Ile31, Ile86 | ||
Melanoma Stem Cell Marker | ||||
CD117 | 1PKG | NCTD | −6.62 | Ala621, Cys809, Leu799, Lys623, Thr670, Val603 |
PTX | −7.40 | Ala597, Asp810, Asp677, Cys809, Gly596, Leu799, Lys623, Thr6670, Val603 | ||
CD117 (extracellular domain) | 2EC8 | NCTD | −4.90 | Gln346, Pro343 |
PTX | −5.24 | Glu228, Glu368, Leu222, Leu223, Lys342, Thr230, Thr342 | ||
KITLG | 1EXZ | NCTD | −5.56 | Ala147, Arg13, Gly151, Tyr150, Val73, Val170 |
PTX | −6.01 | Ala147, Arg13, Arg14, Ile152, Ser11, Thr71 | ||
KDM5B | 5A3P | NCTD | −6.52 | Leu716, Met701, Phe700 |
PTX | −5.57 | Asp77, Leu81, Phe438, Pro439, Val440 | ||
Key Drivers of Melanocytic Transformation | ||||
MITF | 4ATK | NCTD | −4.66 | Asp252 |
PTX | −5.53 | Ala249, Lys233, Met239, Pro232, Tyr253 | ||
B-RAF | 4MNF | NCTD | −6.22 | Cys532, Phe583, Trp531 |
PTX | −7.44 | Lys483, Ala481, Asp594, Gly466, Lau514, Phe583, Thr529 | ||
RAF-MEK1 complex | 4MNE | NCTD | −6.34 | Leu74, Leu197, Met146 |
PTX | −7.33 | Asp208, Gly210, Lys97, Met219, Leu215, Phe209 | ||
ERBB2 | 2A91 | NCTD | −6.01 | Pro279, Phe270, Ans467 |
PTX | −6.73 | Asn467, Gly443, Leu28, Tyr280, Val4 | ||
NRAS GTPase | 6E6H | NCTD | −5.91 | Asp13, Gly15, Lys16, Ser17, Val14 |
PTX | −6.61 | Asp13, Ala18, Ala146, Lys117, Lys147, Phe28, Ser17 | ||
Vascularization and Angiogenesis | ||||
HIF1A | 3HQR | NCTD | −7.83 | Arg383, Ile327, His374, Thr387, Val376 |
PTX | −6.34 | Arg322, Ile251, Leu240, Tyr310, Val241, Val314 | ||
VEGF-A | 2VPF | NCTD | −4.53 | Ile46, Phe36, Phe47 |
PTX | −4.74 | Asp63, Cys61, Cys68, Glu64, Lys107 | ||
EGF | 1IVO | NCTD | −3.51 | Lys48 |
PTX | −4.43 | Gly36, Trp49, Trp50 | ||
TWIST1 | 2MVJ | NCTD | −4.01 | Ala9 |
PTX | −4.04 | Ala6, Ala9, Gly89, Lys10, Ser11 | ||
PDPK1 | 1H1W | NCTD | −6.51 | Phe93, ser94, Val127 |
PTX | −6.41 | Glu130, Lys111, Lys123, Leu113, Ser94 | ||
PTGS2 | 1PXX | NCTD | −6.13 | Val291 |
PTX | −7.33 | Arg44, Leu152, Lys468 | ||
Matrix metalloproteinase-1 | 966C | NCTD | −5.90 | Thr241, Val246 |
PTX | −5.53 | Arg214, Asn205, Asn211, his132, his213, Lys136 | ||
Matrix metalloproteinase-2 | 1QIB | NCTD | −6.53 | Leu218, Thr227, Tyr223 |
PTX | −6.83 | Leu164, Tyr223, Val198 | ||
Matrix metalloproteinase-9 | 5UE3 | NCTD | −6.54 | Arg249, His228, Leu222, Leu243, Tyr248 |
PTX | −7.02 | Arg249, His257, Leu243, Thr251 | ||
NF-κB (p50 subunit) | 1SVC | NCTD | −5.42 | Lys147 |
PTX | −5.34 | Lys147, Phe151, Thr205, Val150 |
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Lara-Vega, I.; Nájera-Martínez, M.; Vega-López, A. Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study. Int. J. Mol. Sci. 2025, 26, 7522. https://doi.org/10.3390/ijms26157522
Lara-Vega I, Nájera-Martínez M, Vega-López A. Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study. International Journal of Molecular Sciences. 2025; 26(15):7522. https://doi.org/10.3390/ijms26157522
Chicago/Turabian StyleLara-Vega, Israel, Minerva Nájera-Martínez, and Armando Vega-López. 2025. "Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study" International Journal of Molecular Sciences 26, no. 15: 7522. https://doi.org/10.3390/ijms26157522
APA StyleLara-Vega, I., Nájera-Martínez, M., & Vega-López, A. (2025). Pentoxifylline and Norcantharidin Synergistically Suppress Melanoma Growth in Mice: A Multi-Modal In Vivo and In Silico Study. International Journal of Molecular Sciences, 26(15), 7522. https://doi.org/10.3390/ijms26157522