Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment
Abstract
:1. Introduction
2. Plant-Derived Compounds Inhibit Cell Proliferation, Tumor Growth/Metastasis, and Induction of Programmed Cell Death in TNBC
2.1. Phenolics
2.2. Terpenoids
2.3. Alkaloids
2.4. Other Phytocompounds/Extracts
3. Plant-Derived Compounds Reprogram Cellular Metabolisms and Associated Proteins and Signaling Pathways in Drug Sensitive/Resistant TNBC
4. Plant-Derived Compounds Educate the Tumor Microenvironment and Immune Checkpoints Activity-Associated Signaling Molecules and Pathways
4.1. Regulation of Tumor-Infiltrating Cells, Tumor Cell-Immune Cell Interactions, and Associated Signaling Molecules in the TME
4.2. Regulation of Immune Checkpoint Expression and Activity
4.3. Effects on Exosomes, Epithelial-Mesenchymal Transition and Extracellular Matrix
5. Highlights of Some Clinical Trial Studies for Plant-Derived Drugs against Breast Cancers
6. Current Challenges and Future Prospects for Development of Phytoagents for TNBC Therapy
Compound Alone or in Combination | Molecular Mechanisms/Targets | Preclinical Animal Model | Ref. |
---|---|---|---|
Terpenoids | |||
Monoterpenoids Thymoquinone | ↑p-p38, ROS↑PARP cleavage, TUNEL ↓XIAP, survivin, Bcl-xL, Bcl-2 ↓Ki67, tumor growth | Subcutaneous injection of MDA-MB-231 in nude mice | [56] |
Thymoquinone in liposomal nanoparticles | ↓eEF-2K, Src/FAK, Akt/NF-κB ↑miR-603, ↓cell proliferation ↓migration and tumor growth | Orthotopic injection of MDA-MB-231 and MDA-MB-436 in nude mice | [55] |
Thymoquinone-loaded, hyaluronic acid-conjugated copolymer nanoparticles | ↑miRNA-361 ↓Rac1, RhoA, VEGF-A ↓vascularization | Orthotopic injection of 4T1 tumor model in BALB/c mice | [57] |
Thymoquinone + Doxorubicin | ↓XIAP, surviving, Bcl-xL, Bcl-2 ↑TUNEL ↓Ki67, tumor growth | Subcutaneous injection of MDA-MB-231 in nude mice | [56] |
TQFL12 | ↑stabilize AMPKα ↑p-acetyl-CoA, apoptosis ↓cell growth, migration, invasion | Orthotopic injection of 4T1 tumor model in BALB/c mice | [58] |
Sesquiterpene lactones DET/DETD-35 | ↑G2/M cell-cycle arrest, cell apoptosis ↓migration, invasion, motility ↑cytoplasmic vacuolation ↑exosome release/affect exosomal proteins ↑p-ERK, p-JNK, p-p38 ↑ubiquitinated protein accumulation ↑ER stress-mediated paraptosis and apoptosis, ROS, LC3, | Orthotopic/lung metastatic MDA-MB-231 tumor model in NOD/SCID mice | [63,217] |
DETD-35 + paclitaxel | ↓VEGF, COX-2, Ki67 ↑caspase-3 ↓metastatic pulmonary foci | Lung metastatic MDA-MB-231 tumor model in NOD/SCID mice | [62] |
Artemisinin | ↓TGF-β mRNA levels, MDSC, Treg cells ↑TNFα mRNA levels, Tbet ↑CD4+ IFN-γ+ T cells ↑cytotoxic T lymphocytes ↓tumor growth ↑survival | Orthotopic 4T1 tumor model in BALB/c mice | [189] |
Artemisinin Artemisinin-loaded biotin-PEG-PCL polymers | ↑BAX, ratio of BAX/Bcl-2 ↓tumor growth ↑BAX, ratio of BAX/Bcl-2;↓Bcl-2 ↓tumor growth | 4T1 tumor model in BALB/c mice | [67] |
Artesunate + irinotecan in phosphatidylcholine-based liposomes | ↓tumor growth | 4T1 tumor model in BALB/c mice | [70] |
Dihydroartemisinin + docetaxel in a pH-sensitive nanoparticle delivery system | ↑ROS, p53, cytochrome c release;↓Bcl-2 ↑caspase-3 ↓mitochondrial membrane potential ↓tumor growth;↓metastasis | Orthotopic injection of 4T1 tumor model in BALB/c mice | [66] |
Dihydroartemisinin Dihydroartemisinin+ docetaxel in disulfide-linked nanoparticle delivery system | ↑early apoptosis ↑cell cycle arrest ↓tumor growth ↑cell cycle arrest ↑early apoptosis ↑sustained release, circulating time ↓migration, tumor growth ↑prolonged survival | Orthotopic injection of 4T1 tumor model in BALB/c mice | [65] |
Diterpenoids Paclitaxel Paclitaxel + tyrosine kinases inhibitor (E-3810) | ↑caspase-3/7 activity ↑ECM remodeling, ↓tumor growth ↑caspase-3/7 activity ↑ECM remodeling, MMP-9 ↓tumor growth | Subcutaneous injection of MDA-MB-231 and MX-1 tumor model in nude mice | [222] |
Triptolide | ↓HMGB1, TLR4, p-NF-κB ↓cell viability, clonogenic ability ↓Tumor growth | Subcutaneous injection of MDA-MB-231 tumor model in nude mice | [76] |
↓CD206, Arginase-1, CD204 ↓M2 TAM ↓anti-inflammatory cytokines ↓tumor growth | Orthotopic injection of 4T1 tumor model in BALB/c mice | [190] | |
↓VEGF-A, angiogenesis ↓ERK1/2, HIF1-α ↓tumor growth, tumor cell proliferation | Orthotopic injection of MDA-MB-231 tumor model in nude mice | [196] | |
Polyphenols | |||
Curcumin | ↑miR181b ↓CXCL-1 and CXCL-2 ↓lung metastasis | Intracardiac injection of human MDA-MB-231 cells in immunodeficient mice | [184] |
↓Ki67 ↓VEGFR2/3 ↓micro-vessel density | Subcutaneous injection of human MDA-MB-231 cells in immunodeficient mice | [194] | |
Curcumin (before tumor inoculation) + Listeria-Mage-b vaccine (therapeutic immunization) | ↓IL-6 by MDSCs in tumor/blood ↑IL-12 by MDSCs in blood ↑IFNγ by CD4+ and CD8+ T cells in blood | Orthotopic injection of 4T1 cells in BALB/c mice | [182] |
Curcumin + metformin | ↑tumor apoptosis ↑Serum IL-4 | Subcutaneous injection of EMT6/P cells in BALB/c mice | [183] |
Curcumin + arabinogalactan | ↓Ki67 ↑p53 | Subcutaneous injection of 4T1 cells in BALB/c mice | [30] |
Curcumin + calcitriol | ↓micro-vessel density | Subcutaneous injection of MBCDF-T cells in nude mice | [195] |
Meriva administered after cryoablation | ↓IL-6 | Orthotopic injection of 4T1 cells in BALB/c mice | [185] |
Resveratrol | ↓lung nodules ↓plasma MMP-9 | Intravenous injection of 4T1 cells to develop lung metastasis in BALB/c mice | [219] |
↓MMP-2, MMP-9, vimentin, snail1, slug ↑E-cadherin | Orthotopic injection of human MDA-MB-231 cells in a xenograft model | [210] | |
↑IFNγ and IL-2, M1 TAM in the lung ↑lung-filtrating CD4+ and CD8+ T cells ↑perforin/granzyme on splenic CD8+ T cells ↓PD-1 on pulmonary CD4+ and CD8+ T cells | Intravenous injection of 4T1 cells to develop lung metastasis in BALB/c mice | [200] | |
↓Bregs, TGFβ, Treg | Orthotopic injection of 4T1 cells in BALB/c mice | [186] | |
↓FASN expression ↓lipid synthesis | Orthotopic injection of human MDA-MB-231 cells in nude mice | [130] | |
a 5-LOX inhibitor ↓COX-2 and MMP-9 expression | Rats treated with DMBA to induce mammary cancer | [43,44] | |
↑LC3-II, Beclin1 and Atg 7 in BCSCs ↓Wnt/β-catenin signaling pathway in BCSCs | Orthotopic injection of human SUM159 cells in NOD/SCID mice | [46] | |
Resveratrol + tamoxifen | ↓acetylated STAT3 ↑ER-α gene expression | Subcutaneous injection of human MDA-MB-231 cells in nude mice | [42] |
Resveratrol + cisplatin | ↓p-AKT, p-PI3K, Smad2, Smad3, p-JNK, p-ERK, and NF-κB in tumor tissues | Orthotopic injection of human MDA-MB-231 cells in a xenograft model | [211] |
EGCG | ↓CD44+ BCSCs ↓VEGF ↓MMP-2 ↑Caspase-3 | Rats treated with 7,12 dimethylbenzanthracene (DMBA) to induce mammary cancer | [48] |
↓RNA levels of cyclin D1 (CCND1), RHOC, fibronectin (FN1), E-cadherin (CDH1), vimentin (VIM) and BCL-XL ↓VEGF expression ↓tumor sphere formation | Orthotopic injection of human ALDH-positive SUM-149 cells in NOD/SCID mice | [49] | |
↓CSF-1, CCL-2, IL-6, and TGFβ ↓infiltration of M2 TAM | Subcutaneous injection of 4T1 cells in BALB/c mice | [216] | |
↓tumor glucose and lactic acid levels ↓tumor VEGF | Subcutaneous injection of 4T1 cells in BALB/c mice | [121] | |
↑CCN5 expression ↓EMT, stemness | Subcutaneous injection of human MDA-MB-231 cells in nude mice | [214] | |
EGCG + taxol | ↑tumor apoptosis ↓tumor GRP78, JNK phosphorylation | Murine breast 4T1 cells in BALB/c mice | [153] |
EGCG + cetuximab | ↓FASN activity | Orthotopic injection of sensitive and chemoresistant TNBC cells | [129] |
Alkaloids | |||
Sacituzumab Govitecan + PARP inhibitors (olaparib or talazoparib) | ↑γ-H2AX | Subcutaneous injection of human BRCA1/2-mutated or—wild-type TNBC cells in nude mice | [86] |
Camptothecin + doxorubicin | ↓M2-like TAMs | Orthotopic injection of 4T1 cells in BALB/c mice | [187] |
Camptothecin-loaded nanoparticle displaying cetuximab | ↓Ki67 | Orthotopic injection of bone-metastatic MDA-MB-231 cells in NSG mice | [77] |
bevacizumab + CRLX101 (a nanoparticle–drug conjugate containing camptothecin) | ↓HIF1α ↓hypoxia | Orthotopic injection of highly aggressive variant MDA-MB-231 cells (LM2-4) in SCID mice | [79] |
Etoposide + TMU-35435 | ↑LC3, γ-H2AX, caspase-3 | Orthotopic injection of 4T1 cells in BALB/c mice | [91] |
Etoposide + TRAIL | ↑DR5 expression ↑PARP, caspases and p53 expressions | Orthotopic injection of human MDA-MB-231 cells in a xenograft model | [93] |
Berberine | ↓TGF-β1 ↓MMP-2 | Orthotopic injection of MDA-MB-231 or 4T1 cells in mice | [220] |
↓Ki67 ↑caspase-9 | Orthotopic injection of MDA-MB-231 cells in nude mice | [221] | |
Berberine binds to VASP Secondary structure of VASP changes ↓actin polymerization | Subcutaneous injection of human MDA-MB-231 cells in nude mice | [98] | |
↓NF-κB, IL-1β, IL-6 and TNFα ↓PCNA | Rats treated with DMBA to induce mammary cancer | [232] | |
Berberine + anti-DR5 antibody | ↑caspase-3 ↑PARP | Orthotopic injection of 4T1 cells in BALB/c mice | [99] |
co-loaded liposome of berberine and doxorubicin | ↓cardiotoxicity ↓tumor | Subcutaneous injection of 4T1 cells in BALB/c mice | [188] |
Plant extracts/other phytocompounds | |||
Sulforaphene | ↓cell proliferation ↓cyclin B1, Cdc2 ↑G2/M phase arrest, Egr1 | Orthotopic injection of MDA-MB-453 tumor model in nude mice | [100] |
↓CRIPTO-1/TDGF1 ↓CRIPTO-3/TDGF1P3 ↓Nanog, ALDH1A1, Wnt3, Notch 4 | Orthotopic injection of MDA-MB-231 tumor model in nude mice | [101] | |
Sulforaphene Sulforaphene + doxorubicin | ↓cell growth, HDAC6;↑autophagy ↑membrane translocation ↑acetylation modification of PTEN synergistic inhibition on MDA-MB-231 xenografts growth. | Orthotopic injection of MDA-MB-231 tumor model in nude mice | [102] |
Sulforaphene Sulforaphene + docetaxel | ↓NF-κB p65 translocation;↓p52 ↓mammosphere formation ↓taxane-induced ALDH+ cell enrichment ↓primary tumor volume ↓secondary tumor formation | Orthotopic injection of SUM149 tumor model in NOD/SCID mice | [103] |
P2Et (Caesalpinia spinosa extract) | ↑mitochondrial membrane potential loss ↑phosphatidylserine externalization ↑caspase 3 activation, IL-6, MCP-1 ↑DNA fragmentation ↓clonogenic capacity of 4T1 cells ↓tumor growth, spleen metastasis | Orthotopic injection of 4T1 tumor model in BALB/c mice | [104] |
↑calreticulin, ATP secretion ↑HMGB1 translocation ↑IL-2, TNFα, IL-4, IL-5 ↑IFNγ-producing CD4+ and CD8+ T cells | Orthotopic injection of 4T1 tumor model in BALB/c mice | [191] | |
↓cell viability, proliferation ↓tumor growth | Orthotopic injection of MDA-MB-468 tumor model in NSG mice | [107] | |
Prophylactic therapy of P2Et | ↑CD4+ T, CD8+ T, NK, DC ↑Treg, MDSC, plasma IL-6 | orthotopic injection of 4T1 tumor model in BALB/c mice | [192] |
P2Et + antiPD-L1 | ↓tumor growth, granulocytes | orthotopic injection of 4T1 tumor model in BALB/c mice | [193] |
Compound Alone or in Combination | Molecular Mechanisms/Targets | Treatment Results | Phase; Intervention | Ref. |
---|---|---|---|---|
Terpenoids | ||||
Artesunate as add-on therapy | Anticancer ↓TGF-β mRNA levels, MDSC, Treg cells ↑TNFα mRNA levels, Tbet ↑CD4+ IFN-γ+ T cells ↑cytotoxic T lymphocytes ↓tumor growth ↑survival | The pharmacokinetics of artesunate and its metabolites—dihydroartemisinin was well described by a combined drug-metabolite model. The saliva sampling for artesunate monitoring of dihydroartemisinin was suggested. | ARTIC-M33/2 Metastatic breast cancer patients (phase I, n = 23) 100, 150, or 200 mg oral artesunate daily as add-on therapy to their guideline-based oncological therapy. | [189,226] |
Anticancer ↓TGF-β mRNA levels, MDSC, Treg cells ↑TNFα mRNA levels, Tbet ↑CD4+ IFN-γ+ T cells ↑cytotoxic T lymphocytes ↓tumor growth ↑survival | The continuous intake of artesunate for 4 weeks in doses up to 200 mg daily was well tolerated in test patients. However, a temporary dose-limiting vertigo was observed in three patients. | ARTIC-M33/2 Metastatic breast cancer patients (phase I, n = 23) 100, 150, or 200 mg oral artesunate daily as add-on therapy to their guideline-based oncological therapy. | [189,227] | |
Anticancer ↓TGF-β mRNA levels, MDSC, Treg cells ↑TNFα mRNA levels, Tbet ↑CD4+ IFN-γ+ T cells ↑cytotoxic T lymphocytes ↓tumor growth ↑survival n | 200 mg/d are recommended for phase II/III trials. | ARTIC-M33/2 Metastatic breast cancer patients (phase I, n = 23) 100, 150, or 200 mg oral artesunate daily as add-on therapy to their guideline-based oncological therapy. | [189,228] | |
Anticancer ↓TGF-β mRNA levels, MDSC, Treg cells ↑TNFα mRNA levels, Tbet ↑CD4+ IFN-γ+ T cells ↑cytotoxic T lymphocytes ↓tumor growth ↑survival | In 13 patients with metastatic breast cancer, up to 200 mg/d long-term oral artesunate in up to 1115 cumulative treatment days (cumulative doses up to 167.3 g) did not result in any major safety concerns. | ARTIC-M33/2 Metastatic breast cancer patients (phase I, n = 23) 100, 150, or 200 mg oral artesunate daily as add-on therapy to their guideline-based oncological therapy. | [189,229] | |
Paclitaxel + Atezolizumab (anti-PD-L1) | Targeting microtubule and PD-L1 | The median OS of 25.4 months (19.6–30.7 months) with Paclitaxel + Atezolizumab (n = 185) and 17.9 months (13.6–20.3 months) with Paclitaxel + Placebo + nP (n = 184) in PD-L1 IC-positive population (n = 369). | Metastatic TNBC Patients (Phase III); nab-paclitaxel (100 mg/m2 of body surface area on days 1, 8, and 15 of every 28-day cycle) was combined with either placebo (n = 451) or atezolizumab (840 mg on days 1 and 15 of each cycle, n = 451). | [17] |
Paclitaxel + iniparib (PARP inhibitor) | Targeting microtubule and PARP | pCR rate was similar among the three arms (21, 22, and 19% for PTX, PWI, and PTI, respectively). pCR in breast and axilla (21, 17, and 19%); best overall response in the breast (60, 61, and 63%); and breast conservation rate (53, 54, and 50%). | 141 TNBC patients with Stage II-IIIA TNBC were randomly assigned to receive paclitaxel (80 mg/m2, d1; n = 47) alone (PTX) or in combination with iniparib, either once-weekly (PTW (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. | [224] |
Paclitaxel + Tigatuzumab (anti-DR5) | Targeting microtubule and DR5 ROCK1 gene pathway activation | 3 CR, 8 PR; 1 almost CR, 11 SD, and 17 PD in the combination arm (ORR, 28%). No CRs, 8 PRs, 4 SDs, and 9 PDs in the Paclitaxel arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS in the combination arm. | TBNC patients (Phase II) A treatment cycle was defined as 4 weeks. Patients received intravenous nab- aclitaxel on days 1, 8, and 15 (100 mg/m2) at 28 days interval with (n = 39) or without (n = 21)) Tigatuzumab intravenously on days 1 and 15 of every cycle (10 mg/kg loading dose followed by 5 mg/kg every other week). | [225] |
Polyphenols | ||||
Curcumin + docetaxel | ↓carcinoembryonic antigen ↓VEGF ↓P-glycoprotein (P-gp, MDR1) | Five patients had PR, and three patients had SD at least 6 w after the last cycle of treatment. ORR was up to 50%. no progressive disease was observed. | Metastatic breast cancer patients (phase I, n = 14) docetaxel (IV 100 mg/m2) every 3 week on day 1 for 6 cycles + curcumin (p.o. 500 mg/day) for 7 consecutive days by cycle | [155] |
Alkaloids | ||||
Sacituzumab Govitecan | Targeting TOP1 in the Trop-2-positive cells | Median PFS was 5.5 months, and median OS was 13 months. ORR was 33%. | refractory metastatic TNBC patients (phase I/II, n = 108) 10 mg/kg, intravenously on days 1 and 8 of each 21-day cycle | [83] |
Median PFS was 5.6 months, and median OS was 12.1 months. ORR was 35%. | Metastatic TNBC patients (phase III, n = 468) 10 mg/kg, intravenously on days 1 and 8 of each 21-day cycle | [82] | ||
Irinotecan + iniparib (PARP inhibitor) | Targeting TOP1 and PARP | Median OS was 7.8 months. Intracranial RR was 12%, while intracranial CBR was 27%. | TNBC patients with new or progressive brain metastases (phase II, n = 37) Irinotecan 125 mg/m2 intravenously (IV) on days 1 and 8 of each 21 day cycle. Iniparib was dosed at 5.6 or 8 mg/kg IV on days 1, 4, 8, 11 of each 21 day cycle. | [81] |
Etoposide | Targeting topoisomerase II | ORR was 25%. Nine patients achieved SD for more than 24 weeks and CBR was 53%. The median PFS and OS were 5 (range, 1.5–17.0 months) and 16 months (range, 3.0–51.0 months), respectively. | Metastatic breast cancer patients (phase I, n = 32) 60 mg/m2/d on days 1–10, followed by 11 days of rest | [88] |
Seven (9.3%) patients achieved PR and 29 (38.7%) had SD. Nine patients (12%) had SD for >24 weeks and the CBR was 21.3% (16/75). The median PFS was 4.5 (range, 1.3–7.7) months. | Metastatic breast cancer patients (phase II, n = 75) 60 mg/m2/d on days 1–10, followed by 11 days of rest | [89] | ||
Median PFS was 4 months, CBR was 18% (overall response rate 4%), and median OS from the start of treatment was 11 months. | Metastatic breast cancer patients (phase II, n = 75) 50 mg/day in 20-day cycles with 1-week of rest | [90] |
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Wu, T.-N.; Chen, H.-M.; Shyur, L.-F. Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 13571. https://doi.org/10.3390/ijms222413571
Wu T-N, Chen H-M, Shyur L-F. Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment. International Journal of Molecular Sciences. 2021; 22(24):13571. https://doi.org/10.3390/ijms222413571
Chicago/Turabian StyleWu, Tai-Na, Hui-Ming Chen, and Lie-Fen Shyur. 2021. "Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment" International Journal of Molecular Sciences 22, no. 24: 13571. https://doi.org/10.3390/ijms222413571
APA StyleWu, T.-N., Chen, H.-M., & Shyur, L.-F. (2021). Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment. International Journal of Molecular Sciences, 22(24), 13571. https://doi.org/10.3390/ijms222413571