Phytoconstituents as emerging therapeutics for breast cancer: Mechanistic insights and clinical implications

Abstract

Breast cancer remains one of the leading causes of cancer-related morbidity and mortality among women worldwide, necessitating the development of novel therapeutic strategies. Phytoconstituents, naturally plant-derived bioactive compounds, have emerged as promising agents for breast cancer therapy due to their multifaceted mechanisms of action. This review examines the role of phytoconstituents in inducing apoptosis, inhibiting breast cancer cell proliferation, and suppressing metastasis. Furthermore, the anti-angiogenic effects of these compounds are discussed, highlighting their potential to disrupt tumor vascularization. We also summarize the in vitro and in vivo study-derived preclinical evidence supporting the efficacy of phytoconstituents. The synergistic potential of phytoconstituents with conventional therapies is also explored, emphasizing their ability to enhance treatment efficacy while minimizing adverse effects. We also address the challenges and limitations in the clinical application of phytoconstituents, paving the way for future research. This review provides insights into the therapeutic potential of phytoconstituents in breast cancer and their underlying mechanisms, advocating for their integration into existing treatment regimens.

Keywords: Angiogenesis inhibition; Apoptosis; Breast cancer; Cell proliferation inhibition; In vitro studies; In vivo studies; Nanotechnology drug delivery system; Neoplasm metastasis; Phytochemicals; Preclinical studies.

Graphical abstract

Figure 1

Chemical structures and plant sources of bioactive compounds with anti-breast cancer activity.

Figure 2

Mechanistic role of phytochemicals in cancer pathways. This figure shows how phytochemicals regulate key cancer-related processes. Phytochemicals inhibit survival signaling pathways such as JAK/STAT, NF-κB, PI3K/AKT/mTOR, ERK/MAPK, and Wnt/β-catenin. They promote apoptosis by activating cysteine-aspartic proteases (caspases), Bcl-2/Bax, DR4, XIAP, and Bim. Phytochemicals cause cell cycle arrest by regulating cyclins (cell cycle regulators), CDKs, and cell cycle inhibitors such as p21, p27, and p53. They promote autophagy by targeting FoxO1 and LC3-II. Phytochemicals inhibit metastasis by suppressing EMT, MMPs, and uPA. They reduce angiogenesis by inhibiting VEGF and regulate epigenetic alterations through miRNAs, DNA methylation, and histone deacetylation (removal of acetyl groups from histone proteins). Arrows indicate the actions of phytochemicals: green for promotion, red for inhibition, and orange for regulation. AKT: Protein kinase B; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; Bim: Bcl-2-like protein 11; CDK: Cyclin-dependent kinase; DR4: Death receptor 4; EGFR: Epidermal growth factor receptor; EMT: Epithelial-to-mesenchymal transition; ERK: Extracellular signal-regulated kinase; FoxO1: Forkhead box O1; JAK: Janus kinase; LC3-II: Microtubule-associated protein light chain 3-II; MAPK: Mitogen-activated protein kinase; miRNA: micro RNA; MMP: Matrix metalloproteinase; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; Notch-1: Neurogenic locus notch homolog protein 1; p21: Cyclin-dependent kinase inhibitor 1; p27: Cyclin-dependent kinase inhibitor 1B; p53: Tumor suppressor protein; PI3K: Phosphoinositide 3-kinase; STAT: Signal transducer and activator of transcription; uPA: Urokinase-type plasminogen activator; VEGF: Vascular endothelial growth factor; Wnt: Wingless-related integration site; XIAP: X-linked inhibitor of apoptosis protein.

Figure 3

Schematic of extrinsic and intrinsic apoptotic pathways. This figure illustrates the two major pathways of apoptosis: the extrinsic and intrinsic pathways. The extrinsic pathway (left) is triggered by external signals via death receptors, leading to the recruitment of FADD and TRADD proteins, which activate pro-caspase-8. Active caspase-8 further activates caspase-3/7, resulting in apoptosis. Regulators, such as TRAF2, cIAPs, and RIP are involved in this process, with IAP antagonists blocking cIAP activity. The intrinsic pathway (right) is initiated by internal stress signals, such as chemicals, radiation, or growth factor withdrawal. This activates BH3-only proteins, which trigger pro-apoptotic proteins BAK, causing mitochondrial release of cytochrome c. Cytochrome c binds to Apaf-1, leading to the activation of caspase-9, which subsequently activates caspase-3/7. Anti-apoptotic proteins, such as Bcl-2, Bcl-xL, and MCL-1 inhibit this process. BID links the extrinsic and intrinsic pathways by activating tBID. Inhibitors, such as XIAP and cIAPs suppress caspase activity, while SMAC counteracts this inhibition. Non-degradative Ub is shown in blue, degradative ubiquitin in red, and cytochrome c in purple. Apoptosis is the final result of caspase activation. Apaf-1: Apoptotic protease activating factor-1; BAK: Bcl-2 antagonist killer; Bax: Bcl-2-associated X protein; BCL-2: B-cell lymphoma 2; BCL-xL: B-cell lymphoma-extra large; BH3: Bcl-2 Homology 3; BID: BH3-interacting domain death agonist; cIAP: Cellular inhibitor of apoptosis proteins; FADD: Fas-associated death domain; Fas: Fas Cell Surface Death Receptor; IAP: Inhibitor of apoptosis protein; MCL-1: Myeloid cell leukemia 1; p53: Tumor suppressor protein; RIP: Receptor-interacting protein; SMAC: Second mitochondria-derived activator of caspases; tBID: Truncated BH3-interacting domain death agonist; TNF: Tumor necrosis factor; TRADD: Tumor necrosis factor receptor-associated death domain; TRAF2: Tumor necrosis factor receptor-associated factor 2; Ub: Ubiquitin; XIAP: X-linked inhibitor of apoptosis protein.

Figure 4

Schematic representation of the mechanism by which curcumin modulates apoptosis and inflammatory signaling pathways. Curcumin inhibits NF-κB and STAT3, reducing the expression of IL-6. This leads to decreased activation of the JAK pathway and subsequent suppression of downstream inflammatory and anti-apoptotic signaling. Additionally, curcumin downregulates MMP and anti-apoptotic proteins, such as Bcl-2, while promoting pro-apoptotic proteins, such as Bax. These effects enhance apoptosis and reduce the expression of EMT markers, including TWIST, SNAIL, and SLUG. Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; EMT: Epithelial-to-mesenchymal transition; IL-6: Interleukin-6; JAK: Janus kinase; MMP: Matrix metalloproteinase; NF-κB: Nuclear factor kappa B; P: phosphorylated SLUG: Snail family transcriptional repressor; SNAIL: Snail family transcriptional repressor; STAT3: Signal transducer and activator of transcription 3; TWIST: Twist family BHLH transcription factor.