Azadirachta indica (Neem) as an Adjunctive Therapeutic in Breast Cancer: Insights into Apoptosis and Angiogenesis Inhibition

Abstract

Breast cancer remains a leading global malignancy, with persistent challenges in chemoresistance, recurrence, and therapy-related toxicities, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). Adjunctive therapies from natural products offer multitargeted strategies to enhance efficacy and mitigate adverse effects. Azadirachta indica (neem), a cornerstone of Ayurvedic medicine, emerges as a promising candidate due to its rich phytochemical profile, including limonoids (nimbolide, azadirachtin, gedunin) and flavonoids (quercetin), which exhibit pleiotropic anticancer activities. This review synthesizes evidence on neem's adjunctive potential in breast cancer, focusing on its induction of apoptosis via intrinsic/extrinsic pathways (Bax/Bcl-2 modulation, caspase activation, p53 upregulation) and inhibition of angiogenesis through VEGF/HIF-1α suppression and MMP downregulation. Preclinical studies demonstrate subtype-agnostic cytotoxicity (IC50 2–50 μM in MCF-7/MDA-MB-231 models), tumor regression in xenografts (35–65%), and synergies with doxorubicin/cisplatin (CI <0.8), without compromising normal cells. Limited clinical data from Phase I trials in other cancers affirm tolerability (no DLT at 1,000 mg/day), with observational breast cohorts showing improved wound healing and quality of life. Pharmacokinetic hurdles (F <5%) are addressable via nanoformulations. Despite standardization challenges and sparse RCTs, neem's low toxicity and mechanistic synergy position it as a viable adjunct, warranting Phase II trials to bridge traditional wisdom with precision oncology for equitable care.