Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro
Abstract
:1. Introduction
2. Results
2.1. Cytotoxic Effects on Health Cells
2.2. Antitumor Effects
2.2.1. Anti-Proliferative Activity
2.2.2. Pro-Apoptotic Activity
2.2.3. Sensitization of Cancer Cells to DOCE Growth-Suppressive Effect
2.2.4. Colony Formation Test
2.2.5. Cell Migration Assay
2.2.6. Gene expression
- Sensitization of cancer cells to DOCE growth-suppressive effect
- CAT and ProB2-induced anti-migratory effect
3. Discussion
- It is considered that the binding affinity of CATs to ERβ and ERα is likely conditioned by the structure and the dose as well as the cell type [66,68,69,72]. CAT it is a flavan-3-ol, whose family is considered structurally similar to isoflavones that exhibit some structural similarities with 17-b-estradiol as well as with other steroid hormones and steroid hormone antagonists. Thus, CAT could act as an ER agonist or antagonist whose action is both ER concentration- and ER isomorph-dependent or flavane type-dependent. The number of hydroxyl groups, mainly those in the flavonoid B-ring, appeared to be of importance, while changes in the A- or B-hydroxylation rings are given minor importance [82,83].
- Different CATs can antagonize androgen, resulting in a decrease in AR-mediated transcriptional activation [74]. Furthermore, Kampa et al. [75] suggested that flavanol dimers B1-B4 (oligomeric Pro) and in particular, oleylated B2 could be considered a therapeutic agent for advanced PC since it had a powerful agonist effect on membrane AR in androgen-independent DU145 PC cells (ProB2 > ProB3 = ProB4 > ProB1).
- In the present study, we observed that MCF-7 and DU145 cells were most sensitive to ProB2 and/or CAT than the remaining BC and PC cells, respectively. It is known that MCF-7 cells and T47D cells both are ER+, PR+ AR+ cells, but MCF-7 cells differ from T47D cells in that they continually express ER while T47D cells lose ER and PR expression under estrogen withdrawal [85] as well as in ER and PR expression levels [29,86]. Additionally, AR activity is necessary for ER+/AR+ MCF-7 and T47D cell line growth [87]. MCF-7 and T47D both express AR, but two different regulatory pathways may be involved in the androgen-induced stimulation of proliferation, resulting in different repercussions on proliferative activity. MCF-7 cells show AR-mediated and AR-independent MCF-7 mechanisms, whereas T47D exhibits an AR-mediated one. In addition, MCF-7 cells express a wild-type AR characterized by a shortened CAG repeat, while T47D presents a CAG repeat length considered in the normal range [88]. This shortening represents a more active receptor [89]. In addition, these cell lines differ in AR-FL (full-length AR) and splice variants from the AR gene (ARVs) expression. The latter are constitutively active androgen-independent transcription factors that are implicated in resistance to treatment in PC and in BC. ARVs vary widely among the BC and PC cell lines tested. As an example, MDA-MB-231 cells exhibits the highest ARV to AR-FL ratio, followed by T47D and MCF-7 cells. Additionally, MDA-MB-231 cells exhibit low AR-FL and high AR-V3 expression. AR45, AR-V1, AR-V7 and AR-V9 splice variants rather than T47D and MCF-7 cells [90]. On the other hand, DU145 and PC3 cells do not express AR and Erβ, while PC3 express ERα [91].
- Additionally, it should be remembered that MCF7 and T47D are PR+. Regarding PC cells lines used in the present study, PC3 and DU145 differ in the expression of PR isoforms (isoforms A and B). While PC3 presents the two promotors methylated and inactivated, DU145 presents them unmethylated and activated. It should be noted that two promoters control the expression of PR isoforms and hypermethylation of cytosine-rich areas in promoters, which is considered a functional inactivation [92]. The overexpression of the isoform A is involved in cyclin D1 activity; proliferative promoters increase (TGFβ1) as well as pro-invasive and pro-migratory changes (basal membrane disruption, etc.). Interestingly, those effects can be counteracted by antiestrogens [93].
- Grape seed extracts and red wine, and specifically ProB2 dimers (from grape seeds as well as red wine), could suppress aromatase activity [76,77,78,79], inducing hormonal changes attributed to AI [79]. DU145 and PC3 cells used in the present study have constitutive aromatase activity, but with different levels [94]. Regarding BC cell lines, there are contradictory data on aromatase expression, with the presence [95,96] or absence of this enzyme [97]. In the present study, we found that PC and BC cell lines show different degrees of susceptibility to the effects of CAT and ProB2.
- 5α-reductase 1 is present in both PC cell lines used in this study, while 5α-reductase 2 is present in DU145 PC cells [98]. With respect to BC cell lines, MCF-7 and T47D BC cells used in this study both express 5α-reductase 1 [99]. It was suggested that some CATs from green tea seed extract exert 5α-reductase inhibitory characteristics. On the other hand, it seems that natural compounds that act as inhibitors possessing a catechol group have selectivity for the type 1 isozyme [80]. Additionally, polymeric anthocyanins seem to be type 2 isozyme inhibitors [81]. Thereby, it was suggested that they are useful for the prevention as well as the treatment of androgen-dependent disorders [80].
- Combined therapy with receptor modulators and chemotherapy drugs such as DOCE has long since been given improving clinical outcomes (CHAARTED trial, STAMPEDE trial, PROXIMA trial, etc.) [59,100,101,102,103]. Moreover, it has recently been found that SERMs can act as modulators of microtubules at taxane sites [104]. As it is shown in Figure 12A–C, ProB2 and/or CAT could exert a pleiotropic effect on hormone receptors and hormone synthesis, in particular in ER+PR+, AR+ BC cells such as MCF-7 cells (already discussed above). Additionally, as it is shown in Figure 12A, CATs and DOCE have some similar mechanisms of action such as AIs or AR modulators. These aspects may have contributed to the sensitizing effect of DOCE in the combined treatment of ProB2 plus DOCE and CAT plus DOCE shown in this study.
- The dual targeting of the microtubule structure could sensitize cancer cells to chemotherapy treatment (Figure 13). Microtubule-targeting agents (MTAs) such as DOCE are an effective treatment for solid tumors such as BC and PC. This drug is the standard treatment for BC and PC, both metastatic and resistant to other treatments [59,60,101,102,103]. A large number of naturally sourced MTAs are antimitotic agents by acting on tubulin protein and its polymers microtubules [105,106]. These drugs can be classified according to their effect in microtubule-destabilizing agents ((MTDAs) vinca alcaloids, cryptophycins, etc.) and microtubule-stabilizing agents (MTSAs) that include Paclitaxel and its semisynthetic analogue DOCE [105], the chemotherapy drug tested in the present study. DOCE binds to the β-tubulin subunits of microtubules at the taxane-binding side, inducing the suppression of MT dynamics (low doses) or the stabilization of microtubules, and thereafter, cell-cycle arrest [105].
- The molecules tested in our study could act as MTAs, and their administration with DOCE could contribute to the sensitization to DOCE by CAT and ProB2 observed in our study (Figure 13). Recent reports suggest that natural compounds such as CATs can exert anti-proliferative activity against parasites [107] and lung, cervix [108] and hepatoma cancer [109] cell lines could be mediated by union to β-tubulin chain [103], α-tubulin protein and α-β heterodimer [109]. In silico modeling has provided additional insights into potential mechanisms of some types of CATs by binding to α-tubulin molecules at the interface, between α-and β-heterodimers, which could be responsible for the depolymerization of MTs in cervix cancer cells. Additionally, a cell-free system study showed that EGCG causes the inhibition of microtubule polymerization [108]. In our future research, we will analyze the effect of ProB2 and CAT, with and without DOCE, on α-and β-tubulin as well as microtubules.
- Among the cells used in this study, the MCF-7 cell line has been shown to be the most sensitive to treatment. Overall, our results suggest that CDKN1A, BAX, CASP9 and E-cadherin up-regulated expression contributing to the ProB2- and CAT-induced sensitization to DOCE in MCF-7 cells, since:
- CDK 1 is of particular importance as it is essential to ensure cell cycle progression and apoptosis [110,111,112]. CDK inhibitors had been postulated as a promising therapeutic strategy for advanced cancer [113]. CDKN1A suppresses tumor growth and apoptosis [41,42,111,113]. It is postulated that preventing the up-regulation of the CDK1 axis improves the sensitivity of cancer cells to chemotherapeutic agents, increasing their effectiveness. Combined treatment with CDK inhibitors and chemotherapeutic agents significantly increases the effectiveness of the chemotherapeutic agent [108,109,110,111,112,113,114,115], including docetaxel [114]. In addition, inactivating CDK1 agents can induce long-term cytotoxicity (clonogenic assay) [116]. In the present study, we observed that MCF-7 cells treated with CAT plus DOCE and ProB2 plus DOCE caused a high increase in CDK1 inhibitor. Additionally, in this study, the combined treatment of PRoB2 plus DOCE as well as CAT plus DOCE inhibited the formation of colonies drastically in relation to DOCE alone.
- BAX and CASP9 promote apoptosis [43,44,45,46,47] and both CASP3 and CASP9 seem to be involved in taxane-induced cell death [46]. Interestingly, we found that both BAX (≈ eight-fold) and (≈ two-fold) increased in CAT plus DOCE-treated cells and ProB2 plus DOCE-treated cells, respectively, in relation to DOCE.
- E-cadherine, an epithelial phenotype maintaining gene, can inhibit mitogenic signaling [48] and its suppression is associated to DOCE chemoresistance in hormonal tumors [49,50,53]. As far as we observed, with a great increase in E-cadherine under combined treatment compared to DOCE single treatment, a highly sensitizing effect could be expected.
- Sensitization to DOCE induced by the compounds tested on MCF-7 cells does not appear to be influenced by the expression of beta tubulin III (TUBB3), baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) and forkhead box protein P3 (FOXOP3). It is known that FOXOP3 is involved in apoptosis [117] and that BIRC5 is a bi-functional protein that acts not only as a mitotic regulator but also inhibits caspase activation [118].
4. Material and Methods
4.1. Cell Culture
4.2. Treatments
4.3. Viability Assay
4.4. Sensitization of Cancer Cells to Growth Suppression by DOCE
4.5. Apoptosis Assay
4.6. Colony Formation Assay
4.7. Cell Migration Assay
4.8. Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR)
4.9. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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(A) | |||||||
DOCE (nM) | ProB2 (µM) | Mean | SD | DOCE (nM) | CAT(µM) | Mean | SD |
0 | 0 | 98.84 | 0.87 | 0 | 0 | 98.01 | 0.87 |
0 | 25 | 98.51 | 0.92 | 0 | 50 | 99.6 | 0.79 |
0 | 50 | 97.83 | 0.65 | 0 | 70 | 98.87 | 0.88 |
0 | 100 | 97.75 | 1.03 | 0 | 80 | 98.32 | 0.86 |
0 | 150 | 96.62 | 0.78 | 0 | 100 | 99.05 | 0.68 |
0 | 200 | 32.22 * | 0.93 | 0 | 150 | 32.8 * | 1.15 |
1 | 0 | 99.11 | 1.11 | 1 | 0 | 97.87 | 0.5 |
1 | 25 | 99.27 | 1.06 | 1 | 50 | 98.67 | 0.74 |
1 | 50 | 98.08 | 0.93 | 1 | 70 | 98.86 | 0.87 |
1 | 100 | 98.45 | 0.68 | 1 | 80 | 99.34 | 0.75 |
1 | 150 | 97.9 | 0.86 | 1 | 100 | 98.43 | 0.67 |
1 | 200 | 27.86 * | 0.92 | 1 | 150 | 24.32 * | 0.87 |
2 | 0 | 98.33 | 1.21 | 2 | 0 | 97.08 | 1.21 |
2 | 25 | 98.08 | 1.23 | 2 | 50 | 98.06 | 1.13 |
2 | 50 | 99.43 | 0.96 | 2 | 70 | 97.97 | 0.94 |
2 | 100 | 98.52 | 0.87 | 2 | 80 | 98.87 | 0.89 |
2 | 150 | 98.31 | 0.79 | 2 | 100 | 99.56 | 1.27 |
2 | 200 | 24.12 * | 0.93 | 2 | 150 | 21.13 * | 0.83 |
(B) | |||||||
DOCE (nM) | ProB2 (µM) | Mean | SD | DOCE (nM) | CAT (µM) | Mean | SD |
0 | 0 | 97.32 | 0.61 | 0 | 0 | 98.33 | 1.17 |
0 | 10 | 98.91 | 0.87 | 0 | 5 | 97.09 | 1.72 |
0 | 25 | 98.10 | 1.13 | 0 | 20 | 99.93 | 1.22 |
0 | 50 | 97.02 | 0.65 | 0 | 30 | 97.53 | 0.96 |
0 | 60 | 42.21 * | 0.83 | 0 | 50 | 98.04 | 0.78 |
0 | 80 | 31.01 * | 1.29 | 60 | 0 | 97.13 | 1.04 |
0 | 100 | 25.47 * | 1.09 | 60 | 5 | 97.21 | 1.62 |
60 | 0 | 95.31 | 1.24 | 60 | 20 | 97.22 | 1.77 |
60 | 10 | 96.04 | 1.20 | 60 | 30 | 98.28 | 0.94 |
60 | 25 | 96.92 | 1.28 | 60 | 50 | 97.67 | 0.79 |
60 | 50 | 97.31 | 0.76 | 120 | 0 | 98.75 | 1.65 |
60 | 60 | 37.06 * | 0.56 | 120 | 5 | 98.59 | 1.31 |
60 | 80 | 29.23 * | 0.72 | 120 | 20 | 98.81 | 0.84 |
60 | 100 | 14.26 * | 0.37 | 120 | 30 | 98.01 | 1.52 |
120 | 0 | 96.72 | 1.36 | 120 | 50 | 97.27 | 1.19 |
120 | 10 | 97.44 | 1.03 | ||||
120 | 25 | 97.03 | 0.74 | ||||
120 | 50 | 96.15 | 0.82 | ||||
120 | 60 | 35.24 * | 0.59 | ||||
120 | 80 | 22.97 * | 0.43 | ||||
120 | 100 | 13.28 * | 0.47 |
Gene Symbol * | Description † | Treatment | Related to Control | Related to DOCE |
---|---|---|---|---|
CDH1 | Cadherin 1, type 1, E-cadherin (epithelial) | DOCE | 0.00770 | |
CAT | 0.51759 | 67.19063 a | ||
ProB2 | 0.10638 | 13.68735 a | ||
CAT+DOCE | 0.30540 | 39.51263 a | ||
ProB2+DOCE | 0.07310 | 9.49801 a | ||
CDKN1A | Cyclin-dependent kinase inhibitor 1A | DOCE | 5.06 a | |
CAT | 1.60 a | 0.97 | ||
ProB2 | 0.22 | 7.39 b | ||
CAT+DOCE | 0.38 | 8.22 b | ||
ProB2+DOCE | 0.49 | 2.40 b | ||
BAX | BCL-2-associated X protein | DOCE | 0.05 | |
CAT | 0.01 | 0.02 | ||
ProB2 | 0.15 | 0.37 | ||
CAT+DOCE | 7.25 a | 8.46 b | ||
ProB2DOCE | 1.37 | 1.92 b | ||
CASP9 | Caspase-9 | DOCE | 18.02465 a | |
CAT | 1.55971 a | 0.08442 | ||
ProB2 | 0.36939 | 0.02025 | ||
CAT+DOCE | 8.27195 a | 0.46528 | ||
ProB2+DOCE | 1.48718 a | 0.08252 |
Cell Line | T. Type a | T. source | Pan-Can | IHC-ST b | Tx-st | Diffs | TP53 Status c | ER/PR/HERB2/AR d |
---|---|---|---|---|---|---|---|---|
MCF-7 | A, NOS | PE | Lum/HER2 | A | Lum | Lum1 | Wt | ER +/PR+/HERB2-/AR+ |
T47D | Idc, NOS | PE | Lum/HER2 | A | Lum | Lum2 | m | ER+/PR+/HERB2-/AR+ |
MDA-MB-231 | A, NOS | PE | ------ | C | Claudin low | ------ | m | ER-/PR-/HERB2-/AR+ |
PC3 | AD, Grade IV | Bom-d | ------ | ------ | ------ | ------ | m | ER/PR/AR- |
DU145 | AD, NOS | Brm-d | ------ | ------ | ------ | ------ | m | ER/PRAR- |
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Núñez-Iglesias, M.J.; Novio, S.; García, C.; Pérez-Muñuzuri, M.E.; Martínez, M.-C.; Santiago, J.-L.; Boso, S.; Gago, P.; Freire-Garabal, M. Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro. Int. J. Mol. Sci. 2021, 22, 7178. https://doi.org/10.3390/ijms22137178
Núñez-Iglesias MJ, Novio S, García C, Pérez-Muñuzuri ME, Martínez M-C, Santiago J-L, Boso S, Gago P, Freire-Garabal M. Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro. International Journal of Molecular Sciences. 2021; 22(13):7178. https://doi.org/10.3390/ijms22137178
Chicago/Turabian StyleNúñez-Iglesias, Mª Jesús, Silvia Novio, Carlota García, Mª Elena Pérez-Muñuzuri, María-Carmen Martínez, José-Luis Santiago, Susana Boso, Pilar Gago, and Manuel Freire-Garabal. 2021. "Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro" International Journal of Molecular Sciences 22, no. 13: 7178. https://doi.org/10.3390/ijms22137178