Harnessing the nutriceutics in early-stage breast cancer: mechanisms, combinational therapy, and drug delivery

Abstract

Background: Breast cancer (BC) is a significant health challenge, ranking as the second leading cause of cancer-related death and the primary cause of mortality among women aged 45 to 55. Early detection is crucial for optimal prognosis. Among various treatment options available for cancer, chemotherapy remains the predominant approach. However, its patient-friendliness is hindered by cytotoxicity, adverse effects, multi-drug resistance, potential for recurrence, and high costs. This review explores extensively studied phytomolecules, elucidating their molecular mechanisms. It also emphasizes the importance of combination therapy, highlighting recent advancements in the exploration of diverse drug delivery systems and novel routes of administration. The regulatory considerations are crucial in translating these approaches into clinical practices.

Results: Consequently, there is growing interest in exploring the relationship between diet, cancer, and complementary and alternative medicine (CAM) in cancer chemotherapy. Phytochemicals like berberine, curcumin, quercetin, lycopene, sulforaphane, resveratrol, epigallocatechin gallate, apigenin, genistein, thymoquinone have emerged as promising candidates due to their pleiotropic actions on target cells through multiple mechanisms with minimal toxicity effects. This review focuses on extensively studied phytomolecules, elucidating their molecular mechanisms. It also emphasizes the importance of combination therapy, highlighting recent advancements in the exploration of diverse drug delivery systems and novel routes of administration. The regulatory considerations are crucial in translating these approaches into clinical practices.

Conclusion: The present review provides a comprehensive understanding of the molecular mechanisms, coupled with well-designed clinical trials and adherence to regulatory guidelines, which pave the way for nutrition-based combination therapies to become a frontline approach in early-stage BC treatment.

Keywords: Breast cancer; Chemotherapy; Complementary and alternative system of medicine; Dietary phytomolecules; Novel drug delivery systems; Nutrition-based combination therapy.

Fig. 1

The morphological difference between breast cancer and normal cells. (Created with BioRender.com)

Fig. 2

A schematic illustration showing the potential anti-tumoral effects exerted by the nutraceuticals of the MD in the breast cancer progression. Bcl-2: B- cell lymphoma 2; CDK: cyclin-dependent kinase; COX-2: cyclooxygenase 2; HIF-1: hypoxia-inducible factor; IL 6: interleukin 6; miR: microRNA; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α: tumor necrosis factor alpha; PDECGF: platelet-derived endothelial cell growth factor; PGE-2: prostaglandin E2; TRAIL: TNF- related apoptosis-inducing ligand; VEGF: vascular endothelial growth factor. This figure was reprinted with permission from Ref [80], Copyright @2021

Fig. 3

Schematic representation of novel routes and formulation approaches for drug delivery in early Breast Cancer (Created with BioRender.com) (HER2, human epidermal growth factor receptor 2; HGFR, Hepatocyte Growth Factor Receptor; EGFR, Epidermal growth factor receptor; P13Kβ, Phosphoinositide 3-kinase beta; mTOR, mammalian Target of Rapamycin (Protein kinase); mdm2, Mouse Double Minute 2; FOXO, Forkhead Box O (Transcription factor); Erβ, Estrogen Receptor Beta; PTEN, Phosphatase and Tensin Homolog (tumour suppressor gene); P53, Tumour protein 53; CDK4/6, Cyclin-Dependent Kinase 4/6; RB, Retinoblastoma; STAT-3, Signal Transducer and Activator of Transcription 3; RAS, Rat Sarcoma (Oncogene); RAF, Rapidly Accelerated Fibrosarcoma ( Protein kinase); MAPK, Mitogen-Activated Protein Kinase; ERK, Extracellular Signal-Regulated Kinase; ER- Estrogen receptor; AP-1, Activator Protein 1(transcription factor); PLCα, Phospholipase C Alpha; PKC, Protein kinase C; IKβ, Inhibitor of Nuclear Factor Kappa-B Kinase Beta (Protein kinase); NF-kβ, Nuclear Factor Kappa β; ERE- Estrogen Response Element)

Fig. 4

Molecular targets of curcumin on ROS, proliferation, apoptosis, and cell phase arrest. HER2, human epidermal growth factor receptor 2; MnSOD, manganese-dependent superoxide dismutase; GGTP, gamma-glutamyltranspeptidase; Nrf-2, nuclear factor 2–related factor; Fen1, Flap structure-specific endonuclease 1; CXCR4, chemokine receptor 4; uPAR, urokinase plasminogen activator receptor; FASN, fatty acid synthase; ACC, acetyl-CoA carboxylase; ICAM-1, intercellular adhesion molecule 1; uPA, urokinase plasminogen activator; MMP-9, matrix metalloproteinase 9; hTERT, telomerase reverse transcriptase; TRAIL, TNF-related apoptosis-inducing ligand. This figure was reprinted with permission from Ref [32], copyright 2016, Society for Laboratory Automation and Screening

Fig. 5

Mechanisms of action frequently exerted by flavonoids in luminal and triple-negative breast cancer. Flavonoids produce numerous biological effects on breast tumor cells, modulating different signaling pathways. Certain flavonoids affect proliferation via cell cycle arrest, trigger apoptosis pathways, generate reactive oxygen species and induce autophagy modulating PI3Kγ signaling, which finally causes a reduction in tumor volume. Also, flavonoids can induce down-regulation of mesenchymal markers (and up-regulation of epithelial markers) via epithelial-mesenchymal transition-related transcription factors and the β-catenin pathway. In addition, tumor cell migration, invasion and angiogenic processes are inhibited through the modulation of metalloproteases, cytoskeletal regulation, vascular endothelial growth factor and aryl hydrocarbon receptor signaling. Some biological processes are inhibited () whereas others are induced () by flavonoids. Signaling pathways involved are highlighted in violet, transcription factors are highlighted in green, and potential targets of certain flavonoids in sky blue. Some flavonoids might act as phytoestrogens and even might show biphasic effects on estrogen receptor α and β. EC: endothelial cell. This figure was reprinted from ref [81], copyright, 2022, Elsevier Masson SAS

Fig. 6

Conventional drug delivery approaches for early Breast Cancer treatment (Created with BioRender.com)

Fig. 7

Schematic representation of novel routes and formulation approaches for drug delivery in early Breast Cancer (Created with BioRender.com)

Fig. 8

Drug delivery systems employed for combined delivery of drugs in Breast Cancer (Created with BioRender.com)