Introduction

The global cancer burden is substantial and rising, and it is projected to continue increasing through 2050, with the disproportionate growth expected in lower-resource regions. [1] The current global statistics for 2022 report approximately 20 million new cancer diagnoses and nearly 10 million cancer-related deaths worldwide. The estimates indicate that nearly one in five men or women develop cancer in a lifetime, whereas around one in nine men and one in 12 women die from it. Demographic projections indicate that annual cancer incidence will reach about 35 million cases by 2050, representing a 77% increase from 2022 levels. [2]

Conventional cancer treatments, including surgery, radiotherapy, chemotherapy, and hormonal therapy, have seen significant advances in both effectiveness and precision. Despite these advances, cancer therapy still faces several major challenges. Chemotherapy and hormone therapy are often limited by resistance caused by genetic mutations, altered signalling pathways, and tumour heterogeneity. [3] These limitations and the ongoing rise in cancer-related deaths underscore the urgent need for alternative therapies. Traditional systems of medicine could help overcome these limitations of conventional medicine, either as standalone therapies or as adjuvants.

Drugs used in traditional systems of medicine are diverse as they might be purely herbal, Herbo-mineral or animal-based. Herbo-mineral formulations (HMFs) are pharmaceutical preparations composed of herbal ingredients combined with purified and processed minerals and/or metals, prepared through classical procedures such as Shodhana (purification) for detoxification and Marana (calcination/incineration) to achieve enhanced therapeutic efficacy. [4,5] HMFs are utilized in various traditional systems of medicine, such as Ayurveda, Siddha, Unani, Traditional Chinese medicine, and Sowa Rigpa (Tibetan medicine). However, this review focuses on Ayurveda and Siddha, which extensively use HMFs and share similar metal-processing techniques in their preparations.

Metallic nanoparticles are emerging as a novel strategy for targeted drug delivery systems and cancer diagnosis. [6] Metals currently employed in nanomedicine include iron, zinc, copper, and noble metals such as gold, silver, and platinum. Recent preclinical studies and early clinical trials suggest that they hold promise for cancer treatment. However, their tendency to accumulate and resist clearance in non-malignant tissues can lead to oxidative stress, metabolic disturbances, macromolecular dysfunction, and ultimately cell death. [7] Green synthesis of nanomedicine offers a cost-effective and eco-friendly alternative to conventional chemical and physical methods. Ayurvedic Bhasma (Herbo-mineral-metallic compounds having mixture of micro or nano particles) can be viewed as analogous to green-synthesized nanoparticles in modern science. The use of plant extracts enhances biocompatibility, stability, safety, and therapeutic potential, making such formulations more effective and environmentally sustainable. [8]

HMFs, described in Ayurveda as Rasaushadhi, have significant advantages over herbal preparations, including smaller therapeutic doses, quicker action, enhanced potency, and a longer shelf life. However, herbal medicines are more widely accepted and have received the attention of researchers across the globe. Evidence regarding the efficacy and safety of HMFs is still limited.

A preliminary literature search identified no published scoping or systematic reviews on the preclinical anticancer effects of HMFs. In vitro and in vivo studies are essential preliminary steps for the scientific validation of the anticancer efficacy and safety of traditional drugs. However, the existing experimental evidence on Ayurveda and Siddha HMFs in cancer is scattered across diverse cancer models, formulations, study designs, and outcome measures, limiting a comprehensive assessment of their therapeutic potential and research gaps. This scoping review aims to systematically map the available evidence, categorize the formulations and experimental approaches studied, and identify knowledge gaps to inform future research and standardization efforts in cancer pharmacology.

Methods

Discussion

The discovery and development of novel drugs originating from natural products have long been a focus of researchers. [12] Majority (>60%) of anticancer drugs used clinically are derived from natural sources such as plants, marine organisms and micro-organisms. [13] The journey of an entirely new drug from laboratory to market approval is a resource-intensive process. Traditional systems of medicine may offer promising therapeutic options for diseases like cancer. By leveraging reverse pharmacology, they circumvent the conventional drug discovery approach.

Over recent years, metal-based nanomaterials have been widely studied for their potential applications in drug delivery systems, especially in the treatment of cancers. Metal nanoparticles offer a model to achieve the main objectives of drug delivery like targeted therapy, minimizing side effects, and controlled drug release. [14] Metal nanoparticles have high drug loading, multifunctionality, and good cellular uptake. However, their use is limited by critical concerns, including potential cytotoxicity, immunogenic responses, inflammation, oxidative stress, long-term accumulation in organs, upscaling from laboratory to industry, high cost of premium-grade metals, or inadequate regulatory frameworks. Consequently, despite encouraging preclinical results, metal nanoparticles often fail in Phase II and Phase III clinical trials. [15]

Traditional HMFs share certain physicochemical features with metal nanoparticles, including nano/submicron particle dimensions and high surface-area-to-volume ratios, as demonstrated by modern characterization studies of several Bhasmas. [16,17] However, HMFs are complex formulations produced through multistep purification and calcination processes and therefore differ from engineered or green-synthesized nanoparticles in composition, surface chemistry, and biological interactions. [8] Nonetheless, HMFs have been used in clinics for centuries to treat a wide range of diseases. Owing to their well-established empirical and clinical foundation, HMFs may offer greater translational success potential.

Nevertheless, traditional medicines are not devoid of safety concerns. Traditional medicines are often perceived as inherently safe and free from adverse effects. However, contrary to this common belief, HMFs present significant safety concerns due to the presence of potentially toxic heavy metals, including lead, mercury, and arsenic. Excessive exposure to these metals may result in cumulative toxicity affecting the nervous, renal, hepatic, and hematopoietic systems. [18,19] Cases of metal toxicity associated with HMFs are primarily attributed to inappropriate use, including excessive doses and prolonged administration, as well as improper preparation procedures. [20] Furthermore, contamination, adulteration, and inadequate quality assurance during production may increase the risk of heavy-metal exposure. Such reports have highlighted the need for stringent quality control and robust post-marketing surveillance. However, ensuring the safety of HMFs remains challenging due to variability in manufacturing practices, difficulties in standardization, and inconsistencies in regulatory frameworks governing traditional medicines. [18,21] In India, Ayurvedic, Siddha, and Unani medicines are regulated by the Ministry of Ayush under the Drugs and Cosmetics Act, with pharmacovigilance initiatives established to monitor adverse drug reactions and enhance patient safety. [22] The World Health Organization (WHO) also advocates the inclusion of traditional medicines into pharmacovigilance systems and provides guidelines for their safety monitoring. [23] Therefore, the safe use of HMFs requires stringent raw-material quality control, compliance with Good Manufacturing Practices (GMP), validated detoxification and processing methods, and continuous pharmacovigilance to ensure that toxic metal levels remain within acceptable limits and do not pose undue health risks.

HMFs are classically claimed to be more potent, with longer shelf life, effective in smaller doses and faster acting in comparison to purely herbal drugs. But the scientific evidence regarding the safety, anticancer efficacy and mechanistic studies of HMFs remains insufficient.

This scoping review aims to map the existing preclinical evidence of anticancer effects of HMFs. This review will provide a comprehensive overview of investigated traditional mineral-based drugs, targeted cancer type, experimental models, dosage, and any reported mechanisms of action.

Additionally, this review will highlight the research gap and limitations of the existing studies. A preliminary search across databases indicates that research on the use of HMFs in cancer is confined to only laboratory studies and case reports. Identifying the challenges in translating preclinical research into clinical trials will help shape the work of future researchers. The findings of this review will contribute to bridging the traditional medicine and modern oncology by providing a structured summary of existing evidence. This can guide researchers and clinicians in prioritizing promising drugs for further investigation and potential therapeutic use.

This review is limited to preclinical studies, such as in vitro and animal experiments, because randomized clinical trials are not yet available. Preclinical studies vary widely in quality and methodologies. This scoping review aims to map the available evidence rather than critically appraising study validity in detail. Additionally, the review may be limited by variability in the terminology used to describe HMFs and exclusion of studies on laboratory-synthesized metals and nanoparticles. Despite these limitations, the scoping review approach is well suited to provide the initial groundwork for subsequent research on traditional HMFs.

Supporting information

Acknowledgments

The authors would like to acknowledge the support and guidance by the Director, All India Institute of Ayurveda and Delhi University for providing access to library resources, which facilitated the literature search and preparation of this review protocol.