Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement
Abstract
:1. Introduction
2. Results
2.1. Effects at 24 h: Viability, Proliferation, Vascular Mimicry
2.1.1. Viability and Proliferation
2.1.2. Vasculogenic Mimicry
2.2. Effects at 6 h: ATP, ROS, Mitochondria and Metabolomics
2.2.1. ATP and ROS Levels
2.2.2. Mitochondria Investigation
2.2.3. Metabolomics Analysis
2.2.4. Investigating Carnitine’s Role
2.2.5. Investigating Pro-Apoptotic Caspases, Cell Death and Apoptosis
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Treatment for 24 h: Cell Proliferation, Cell Viability, Vascular Mimicry
4.2.1. Cell Proliferation
4.2.2. MTT Cell Viability Assay
4.2.3. Vasculogenic Mimicry Assay
4.3. Treatment for 6 h: ROS Release, ATP Release, Mitochondria Staining, Metabolomics Profiling
4.3.1. Evaluation of ROS and ATP Production
4.3.2. Mitochondria Investigation: Whole Fluorescence
4.3.3. Mitochondria Investigation: Confocal Cytofluorescence
4.3.4. Metabolomics Analysis
4.4. Analysis of Carnitine Role
4.5. Apoptosis Analyses
4.6. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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N | Metabolite or Metabolite Indicator | Ratio | p Value | Formula |
---|---|---|---|---|
1 | Short-Chain Acyl-Coenzyme A Dehydrogenase (SCAD) Deficiency (NBS) | 12.46 | 3.3−13 | C4/C3 |
2 | Lactate Dehydrogenase Activity | 5.39 | 1.3−7 | Lac/H1 |
3 | Isobutyryl-Coenzyme A Dehydrogenase Deficiency (NBS) | 5.37 | 2.6−11 | C4/C2 |
4 | Monoglyceride 16:1 | 5.16 | 0.005 | |
5 | Asparagine Synthesis | 3.33 | 5.0−7 | Asn/Asp |
6 | Putrescine Synthesis | 2.87 | 0.007 | Putrescine/Orn |
7 | Lysophosphatidyl-choline 17:0 | 2.67 | 0.018 | |
8 | Polyamine Synthesis | 2.45 | 0.023 | (Putrescine + Spermidine + Spermine)/Orn |
9 | Sarcosine Synthesis from Choline | 2.37 | 0.002 | Sarcosine/Choline |
10 | Glutaminolysis Rate | 2.24 | 8.5−6 | (Ala + Asp + Glu + Lac + Suc)/Gln |
11 | Lysophosphatidyl-glycerol 16:1 | 2.07 | 4.6−4 | |
12 | Betaine Synthesis | 2.01 | 0.004 | Betaine/Choline |
13 | Asparagine | 1.96 | 0.012 | |
14 | Phosphatidyl-ethanolamine P-16:0/15:0 | 1.95 | 0.008 | |
15 | Butyrylcarnitine | 1.84 | 0.002 | |
16 | Lysophosphatidyl-choline 16:0 | 1.81 | 0.031 | |
17 | Sphingosine phosphate d18:1 | 1.73 | 4.0−4 | |
18 | 2-Methylbutyrylglycinuria (NBS) | 1.69 | 0.011 | C5/C3 |
19 | Taurine Synthesis | 1.67 | 0.025 | Taurine/Cys |
20 | Gamma-Aminobutyric Acid Synthesis | 1.47 | 0.005 | GABA/Glu |
21 | Methionine Oxidation | 0.85 | 0.017 | Met-SO/Met |
22 | Glycine Synthesis | 0.80 | 1.6−4 | Gly/Ser |
23 | Dihydrolipoamide Dehydrogenase Deficiency (NBS) | 0.71 | 0.008 | Pro/Phe |
24 | 5-Aminovaleric acid | 0.70 | 0.017 | |
25 | beta-Alanine | 0.69 | 0.025 | |
26 | Hydroxyglutaric acid | 0.68 | 0.003 | |
27 | Serine | 0.67 | 0.010 | |
28 | Alanine | 0.63 | 0.031 | |
29 | Taurine | 0.62 | 0.006 | |
30 | Carnitine | 0.60 | 4.4−4 | |
31 | Triacylglyceride 18:1_33:3 | 0.60 | 0.009 | |
32 | Threonine | 0.59 | 0.007 | |
33 | Glutamine | 0.59 | 0.002 | |
34 | Aspartic acid | 0.59 | 0.028 | |
35 | Sum of Amino Acids | 0.59 | 0.004 | |
36 | alpha-Aminoadipic acid | 0.59 | 0.018 | |
37 | trans-4-Hydroxyproline | 0.58 | 0.010 | |
38 | Ratio of Acetylcarnitine to Carnitine | 0.57 | 0.008 | C2/C0 |
39 | Sum of Solely Glucogenic Amino Acids | 0.57 | 0.002 | Ala + Arg + Asn + Asp + Cys + Gln + Glu + Gly + His + Met + Pro + Ser + Thr + Val |
40 | beta-Aminobutyric acid | 0.56 | 0.012 | |
41 | Sum of Non-Essential Amino Acids | 0.56 | 8.9 × 10−4 | Ala + Arg + Asn + Asp + Cys + Gln + Glu + Gly + Pro + Ser + Tyr |
42 | Cysteine Synthesis | 0.55 | 6.0 × 10−4 | Cys/(Ser + Met) |
43 | Glutamic acid | 0.55 | 1.7 × 10−4 | |
44 | Glicine | 0.54 | 0.002 | |
45 | Taurolithocholic acid | 0.51 | 0.013 | |
46 | Carnosine Synthesis | 0.51 | 0.029 | Carnosine/His |
47 | Glutathione Constituents | 0.50 | 1.2 × 10−4 | Glu + Gly + Cys |
48 | Proline | 0.48 | 8.2 × 10−4 | |
49 | Sum of Conjugated Primary Bile Acids | 0.47 | 0.024 | GCA + GCDCA + TCA + TCDCA |
50 | Taurochenodeoxy-cholic acid | 0.46 | 0.019 | |
51 | Beta-Oxidation | 0.44 | 4.8 × 10−4 | (C2 + C3)/C0 |
52 | Sum of Taurine-Conjugated Bile Acids | 0.43 | 0.014 | TCA + TCDCA + TDCA + TLCA |
53 | Malonic Aciduria (NBS) | 0.43 | 1.6 × 10−5 | C3/C2 |
54 | Sum of Sulfur-Containing Amino Acids | 0.43 | 0.002 | Met + Cys |
55 | Short/Branched-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (NBS) | 0.42 | 5.4 × 10−5 | C5/C0 |
56 | Taurodeoxycholic acid | 0.41 | 0.016 | |
57 | Phosphatidyl-choline O-38:3 | 0.39 | 0.023 | |
58 | Phosphatidyl-choline O-36:5 | 0.38 | 0.024 | |
59 | Ornithine | 0.38 | 0.031 | |
60 | Phosphatidyl-choline O-36:3 | 0.38 | 0.020 | |
61 | Phosphatidyl-choline O-38:6 | 0.38 | 0.018 | |
62 | Cysteine | 0.37 | 7.8 × 10−4 | |
63 | Choline | 0.37 | 6.3 × 10−4 | |
64 | Phosphatidyl-choline 36:3 | 0.35 | 0.02 | |
65 | Phosphatidyl-choline 38:4 | 0.35 | 0.022 | |
66 | Phosphatidyl-choline 40:6 | 0.35 | 0.027 | |
67 | Acetylcarnitine | 0.34 | 3.9 × 10−5 | |
68 | Aconitic acid | 0.33 | 5.0 × 10−4 | |
69 | Hexose | 0.32 | 0.013 | |
70 | Phosphatidyl-choline 38:5 | 0.32 | 0.011 | |
71 | Phosphatidyl-choline O-36:4 | 0.32 | 0.008 | |
72 | Taurocholic acid | 0.32 | 0.005 | |
73 | Phosphatidyl-choline 36:4 | 0.31 | 0.009 | |
74 | Phosphatidyl-choline 36:5 | 0.31 | 0.008 | |
75 | Phosphatidyl-choline O-38:4 | 0.31 | 0.007 | |
76 | Phosphatidyl-choline 38:6 | 0.29 | 0.007 | |
77 | Succinic acid | 0.26 | 2.5 × 10−4 | |
78 | Valerylcarnitine | 0.25 | 7.8 × 10−7 | C5 |
79 | Methylmalonic Acidemia (NBS) | 0.25 | 1.8 × 10−5 | C3/C0 |
80 | Sphinganine d14:0 | 0.21 | 0.004 | |
81 | Propionylcarnitine | 0.15 | 8.6 × 10−7 | C3 |
82 | Triacylglyceride 18:1_33:0 | 0.07 | 0.004 | |
83 | Phosphatidyl-inositol (18:1_20:2) | 0.04 | 0.011 |
Enzymes Related to Carnitine Metabolism | Expression in Melanoma vs. Ctrls log2(TPM-1) | Patients’ Survival Hazard Ratio (p < 0.05) |
---|---|---|
Related to carnitine synthesis | ||
TMLD | n.s. | n.s. |
TMABADH | n.s | n.s. |
SHMT1 | n.s | n.s. |
SHMT2 | 6.8 vs. 5.5 * | HR 1.4 (p = 0.02) |
BBOX1 | 0.1 vs. 4.9 * | n.s. |
ALDH9A1 | n.s. | n.s. |
TMLHE | n.s. | n.s. |
ALDH9A1 | n.s. | n.s. |
Carnitine Carriers | ||
SLC22A5 | 2.1 vs. 3.5 * | n.s. |
SLC25A20 | n.s. | n.s. |
SLC22A4 | n.s. | HR 0.66 (p = 0.002) |
SLC22A16 | n.s. | n.s. |
SLC25A29 | 3.9 vs. 5.4 * | n.s. |
SLC16A9 | n.s. | n.s. |
Related to Carnitine Palmitoyltransferases | ||
CPT2 | n.s. | n.s. |
CPT1A | n.s. | n.s. |
CPT1B | 3 vs. 4.2 * | HR 0.74 (p = 0.02) |
CPT1C | n.s. | n.s. |
ACACB | 2.1 vs. 3.9 * | n.s. |
CHKB-CPT1B | n.s. | HR 0.75 (p = 0.03) |
Carnitine O-Acetyltransferase | ||
CRAT | n.s. | HR 1.3 (p = 0.04) |
Carnitine O-Octanoyltransferase | ||
CROT | 2.9 vs. 3.9 * | n.s. |
Related to acethylcanitine metabolism | ||
ACADM | 5 vs. 4 * | n.s. |
ACAD8 | 3.6 vs. 5 * | n.s. |
ACADS | n.s. | n.s. |
ACADVL | 7.5 vs. 9 * | n.s. |
ACADL | 0.1 vs. 2.1 * | n.s. |
Related to carnitine deficiency | ||
HADHA | n.s. | HR = 1.4 (p = 0.009) |
IFT81 | 3.6 vs. 2.7 * | n.s. |
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Scatozza, F.; Giardina, M.M.; Valente, C.; Vigiano Benedetti, V.; Facchiano, A. Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement. Int. J. Mol. Sci. 2024, 25, 3589. https://doi.org/10.3390/ijms25073589
Scatozza F, Giardina MM, Valente C, Vigiano Benedetti V, Facchiano A. Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement. International Journal of Molecular Sciences. 2024; 25(7):3589. https://doi.org/10.3390/ijms25073589
Chicago/Turabian StyleScatozza, Francesca, Maria Miriam Giardina, Carola Valente, Virginia Vigiano Benedetti, and Antonio Facchiano. 2024. "Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement" International Journal of Molecular Sciences 25, no. 7: 3589. https://doi.org/10.3390/ijms25073589