Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. Evaluation of the Chemosensitivity of Primary Cultured STS Cells to Anticancer Drugs
2.2. Expression of MDR-Associated Genes in STS
2.3. Expression of P-Glycoprotein and ABCG2 in Primary Cultures of STS
2.4. Identification of Mutations in Several Genes of ABC-Transporter Family
3. Discussion
4. Materials and Methods
4.1. Methodological Approaches
4.2. Tumor Specimens
4.3. Chemotheraputic Drugs
4.4. Primary Cancer Cell Cultures and Chemosensitivity Assay
4.5. Cytology for Isolated Cell Culture
4.6. Quantitative PCR (Q-PCR)
4.7. Flow Cytometry
4.8. Western Blotting
4.9. Exome Capture, Alignments and Base-Calling
4.10. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drugs | Dox | Ifo | Dox + Ifo | Doc | Gem | Doc + Gem |
Sensitivity index (SI), mean ± SD | ||||||
293 ± 121 | 315 ± 172 | 230 ± 134 | 402 ± 141 | 379 ± 162 | 304 ± 171 | |
p-value means | ||||||
Ifo | 0.51 | - | - | - | - | - |
Dox + Ifo | 0.0038 | 0.0065 | - | - | - | - |
Doc | <0.0001 | 0.0036 | <0.0001 | - | - | - |
Gem | 0.0006 | 0.04 | <0.0001 | 0.45 | - | - |
Doc + Gem | 0.93 | 0.68 | 0.03 | 0.0005 | 0.01 | - |
Characteristics | n, % | Dox | Ifo | Dox + Ifo | Doc | Gem | Doс + Gem |
---|---|---|---|---|---|---|---|
SI, mean ± SD | 70 | 293 ± 120 | 328 ± 167 | 238 ± 130 | 401 ± 145 | 374 ± 164 | 297 ± 172 |
Age | |||||||
<40 >40 | 23 (33%) 46 (67%) | 0.01 * (higher resistance in >40 group) | 0.41 | 0.10 | 0.08 | 0.08 | 0.17 |
Gender | |||||||
Female Male | 33 (47%) 37 (53%) | 0.49 | 0.54 | 0.82 | 0.70 | 0.89 | 0.16 |
Tumor size | |||||||
T1–T2 Т3–Т4 | 38 (54%) 32 (46%) | 0.89 | 0.30 | 0.46 | 0.78 | 0.39 | 0.62 |
Histology types | |||||||
Undifferentiated pleomorphic sarcoma Liposarcoma Synovial sarcoma Others | 24 (34%) 16 (23%) 11 (16%) 19 (27%) | 0.04 * (Undifferentiated pleomorphic sarcoma more resistance) | 0.74 | 0.62 | 0.12 | 0.34 | 0.13 |
Tumor grade | |||||||
G1–G2 G3 | 10 (15%) 56 (85%) | 0.19 | 0.10 | 0.08 | 0.27 | 0.26 | 0.15 |
Newly diagnosed (without NeoCT) vs. Recurrent | 22 (39%) 35 (61%) | 0.11 | 0.59 | 0.18 | 0.63 | 0.92 | 0.86 |
Treatment characteristics | |||||||
Chemotherapy (all patient) | |||||||
No Yes | 34 (49%) 36 (51%) | 0.23 | 0.21 | 0.72 | 0.89 | 0.35 | 0.64 |
Newly diagnosed vs. Newly diagnosed with NeoCT | 22 (59%) 15 (41%) | 0.32 | 0.92 | 0.98 | 0.21 | 0.16 | 0.06 |
Tumor regression grade | |||||||
0–1 2–3 | 17 (73%) 6 (27%) | 0.11 | 0.31 | 0.49 | 0.0014 ** (higher resistance in 2–3 grade group) | 0.25 | 0.06 |
Tumor regression grade after NeoCT | |||||||
0–1 2–3 | 10 (71%) 4 (29%) | 0.053 | 0.29 | 0.55 | 0.008 ** (higher resistance in 2–3 grade group) | 0.053 | 0.03 * (higher resistance in 2–3 grade group) |
YB-1 | ABCB1 | ABCC1 | ABCG2 | MVP | |
---|---|---|---|---|---|
YB-1 | - | 0.13 | 0.08 | 0.19 | 0.36 |
ABCB1 | 0.30 | - | 0.67 | 0.88 | −0.27 |
ABCC1 | 0.55 | <0.0001 | - | 0.68 | 0.07 |
ABCG2 | 0.10 | <0.0001 | <0.0001 | - | −0.17 |
MVP | 0.001 | 0.02 | 0.60 | 0.14 | - |
Characteristics | n, % | mRNA ABCB1 | mRNA ABCC1 | mRNA ABCG2 | mRNA YB-1 | mRNA MVP |
---|---|---|---|---|---|---|
Age | ||||||
<40 >40 | 23 (33%) 46 (67%) | 0.06 | 0.22 | 0.007 ** (high in >40) | 0.48 | 0.54 |
Gender | ||||||
Female Male | 33 (47%) 37 (53%) | 0.10 | 0.16 | 0.34 | 0.20 | 0.52 |
Tumor size | ||||||
T1–T2 Т3–Т4 | 38 (54%) 32 (46%) | 0.71 | 0.80 | 0.94 | 0.13 | 0.19 |
Histology types | ||||||
Undifferentiated pleomorphic sarcoma Liposarcoma Synovial sarcoma Others | 24 (34%) 16 (23%) 11 (16%) 19 (27%) | 0.07 | 0.12 | 0.23 | 0.03 * (high in Undifferentiated pleomorphic sarcoma) | 0.39 |
Tumor grade | ||||||
G1–G2 G3 | 10 (16%) 56 (84%) | 0.26 | 0.58 | 0.32 | 0.53 | 0.73 |
Newly diagnosed (without NeoCT) vs. Recurrent | 22 (40%) 33 (60%) | 0.47 | 0.74 | 0.21 | 0.94 | 0.04 * (low in recurrent) |
Treatment characteristics | ||||||
Chemotherapy (all patient) | ||||||
No Yes | 34 (49%) 36 (51%) | 0.17 | 0.52 | 0.32 | 0.19 | 0.1 |
Newly diagnosed vs. Newly diagnosed with NeoCT | 22 (59%) 15 (41%) | 0.21 | 0.19 | 0.52 | 0.1 | 0.17 |
Tumor regression grade | ||||||
0–1 2–3 | 17 (73%) 6 (27%) | 0.60 | 0.32 | 0.80 | 0.91 | 0.07 |
Tumor regression grade after NeoCT | ||||||
0–1 2–3 | 10 (71%) 4 (29%) | 0.94 | 1 | 0.9 | 0.94 | 0.054 |
Gene | n | Dox | Ifo | Dox + Ifo | Doc | Gem | Doс + Gem |
---|---|---|---|---|---|---|---|
Undifferentiated pleomorphic sarcoma | |||||||
ABCB1 (all patients) | 24 | ns | ns | ns | r = −0.51 p = 0.009 | ns | r = −0.55 p = 0.005 |
ABCB1 (recurrent patients) | 6 | ns | r = −0.90 p = 0.03 | ns | r = −0.94 p = 0.005 | ns | r = −0.77 p = 0.07 |
ABCG2 (all patients) | 23 | ns | ns | ns | r = −0.48 p = 0.02 | ns | r = −0.55 p = 0.006 |
ABCG2 (recurrent patients) | 5 | r = −0.90 p = 0.03 | ns | ns | r = −0.80 p = 0.10 | ns | r = −0.90 p = 0.03 |
MVP (all patients) | 22 | ns | ns | ns | r = 0.49 p = 0.02 | ns | r = 0.49 p = 0.02 |
MVP (patients with NeoCT) | 8 | ns | ns | ns | r = 0.69 p = 0.054 | ns | r = 0.76 p = 0.03 |
Synovial sarcoma | |||||||
ABCC1 (all patients) | 6 | ns | r = 0.90 p = 0.04 | r = 1.0 p < 0.0001 | ns | ns | ns |
ABCG2 (all patients) | 11 | ns | ns | ns | r = 0.60 p = 0.04 | ns | ns |
Characteristics | n = 44, (%) | Pgp-Positive (n, %) | p-Value | n = 36, (%) | ABCG2-Positive (n, %) | p-Value |
---|---|---|---|---|---|---|
Gender | ||||||
Female Male | 22 (50%) 22 (50%) | 3 (14%) 2 (9%) | 0.67 | 13 (36%) 23 (64%) | 2 (15%) 13 (57%) | 0.07 |
Age | ||||||
>40 <40 | 31 (70%) 13 (30%) | 3 (10%) 2 (15%) | 0.41 | 11 (36%) 25 (64%) | 4 (36%) 11 (44%) | 0.56 |
Tumor size | ||||||
Т1–Т2 Т3–Т4 | 28 (64%) 16 (36%) | 3 (11%) 2 (13%) | 0.83 | 20 (56%) 16 (44%) | 9 (45%) 6 (38%) | 0.43 |
Tumor grade | ||||||
G1–G2 G3 | 5 (13%) 34 (87%) | 0 (0%) 5 (15%) | 0.48 | 2 (6%) 34 (94%) | 1 (50%) 13 (41%) | 1.00 |
Histology types | ||||||
Undifferentiated pleomorphic sarcoma | 16 (36%) | 0 (0%) | 0.04 (higher in synovial sarcoma) | 13 (36%) | 5 (38%) | 0.30 |
Liposarcoma | 9 (20%) | 1 (11%) | 11 (31%) | 7 (64%) | ||
Synovial sarcoma | 6 (14%) | 2 (33%) | 8 (22%) | 2 (25%) | ||
Others | 13 (30%) | 2 (15%) | 4 (11%) | 1 (25%) | ||
Treatment characteristics | ||||||
Chemotherapy | ||||||
No Yes | 28 (68%) 14 (32%) | 3 (14%) 2 (20%) | 0.84 | 23 (64%) 12 (36%) | 5 (22%) 9 (75%) | 0.74 |
Tumor regression grade | ||||||
0–1 2–3 | 8 (89%) 1 (11%) | 1 (13%) 0 (0%) | - | 7 (47%) 8 (53%) | 3 (43%) 3 (38%) | 0.48 |
Patient ID | Gender | Age | Histology Types | Gene | Reference Allele (Position) | Sequenced Allele | Mutations |
---|---|---|---|---|---|---|---|
STS 8 | Male | 37 | Synovial sarcoma | ABCA13 | T (chr7:48271819) | A | p.M718K |
A (chr7:48644634) | T | p.L4987F | |||||
STS 22 | Male | 37 | Synovial sarcoma | ABCC6 | T (chr16:16188976) | G | Intron mutation |
STS 24 | Male | 62 | Undifferentiated pleomorphic sarcoma | ABCC6 | T (chr16:16188949) | G | p.H554P |
T (chr16:16188976) | G | Intron mutation | |||||
STS 29 | Female | 70 | Undifferentiated pleomorphic sarcoma | ABCB11 | C (chr2:168944742) | T | p.E825K |
ABCC1 | G (chr16:16090474) | A | p.G844S | ||||
ABCC11 | C (chr16:48176983) | T | p.G1160D | ||||
STS 80 | Female | 43 | Synovial sarcoma | ABCA3 | C (chr16:2323599) | T | Nonsense Mutation |
STS 93 | Female | 32 | Undifferentiated pleomorphic sarcoma | ABCG2 | C (chr4:88113437) | T | p.G354R |
STS 104 | Male | 66 | Undifferentiated pleomorphic sarcoma | ABCA1 | C (chr9:104831048) | A | p.W590L |
ABCA3 | G (chr16:2288133) | A | p.T908I | ||||
STS 106 | Female | 60 | Undifferentiated pleomorphic sarcoma | ABCC11 | T (chr16:48187226) | C | p.M970V |
STS 119 | Male | 67 | Undifferentiated pleomorphic sarcoma | ABCC1 | C (chr16:16131855) | T | p.R1296W |
ABCB1 | G (chr7:87536512) | T | p.N809K |
Drug/Combination | 100% TDC (mg/mL) |
---|---|
Doxorubicin | 3.0 |
Ifosfamide (4-hydroxy-ifosfamide) | 3.0 |
Doxorubicin + ifosfamide | 3.0 + 3.0 |
Docetaxel | 11.3 |
Gemcitabine | 25.0 |
Docetaxel + gemcitabine | 11.3 + 25.0 |
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Moiseeva, N.I.; Laletina, L.A.; Fetisov, T.I.; Makhmudova, L.F.; Manikaylo, A.E.; Fomina, L.Y.; Burov, D.A.; Lesovaya, E.A.; Bokhyan, B.Y.; Zinovieva, V.Y.; et al. Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells. Int. J. Mol. Sci. 2022, 23, 3183. https://doi.org/10.3390/ijms23063183
Moiseeva NI, Laletina LA, Fetisov TI, Makhmudova LF, Manikaylo AE, Fomina LY, Burov DA, Lesovaya EA, Bokhyan BY, Zinovieva VY, et al. Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells. International Journal of Molecular Sciences. 2022; 23(6):3183. https://doi.org/10.3390/ijms23063183
Chicago/Turabian StyleMoiseeva, Natalia I., Lidia A. Laletina, Timur I. Fetisov, Leyla F. Makhmudova, Angelika E. Manikaylo, Liliya Y. Fomina, Denis A. Burov, Ekaterina A. Lesovaya, Beniamin Y. Bokhyan, Victoria Y. Zinovieva, and et al. 2022. "Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells" International Journal of Molecular Sciences 23, no. 6: 3183. https://doi.org/10.3390/ijms23063183