Naturally-occurring bioactive compounds have gathered the attention of many scientists because of their limited cytotoxicity and high specificity (Salehi et al., 2019a). Indeed, plant-derived natural products are extraordinary reservoirs for the identification of various new drugs (Salehi et al., 2019a) with potent therapeutic abilities, used for centuries in traditional medicine for the treatment of different ailments (Atanasov et al., 2015; Marchese et al., 2016; Russo et al., 2016) due to their beneficial health effects (Wolfender et al., 2011; Cragg and Newman, 2013). Briefly, bioactive compounds derived from natural products are developed into either nutraceuticals or pharmaceuticals (Daliu et al., 2019; Munekata et al., 2020) and implemented for the treatment of various diseases for millennia (Sen and Chakraborty, 2017).

Cancer is a multifaceted disease orchestrated by a plethora of cellular processes and signaling cascades (Ahmad Farooqi et al., 2017). Considered a global health concern, the therapeutic options currently available for treating cancer are extremely lethal and provoke organs malfunctioning, which in turn reduces the life expectancy, besides to be extremely expensive (Hugtenburg et al., 2019). Natural products derivatives, such as phytochemicals, have emerged as potential chemopreventive agents able to reduce the risk of tumor initiation, metastasis, invasion, and spread (Zhao et al., 2018). Interestingly, a raising evidence have shown that phytochemicals share similar modes of action with conventional chemotherapeutic agents, and therefore, can be viewed as both adjuvants and therapeutic alternatives to the conventional antitumor therapies (Tiloke et al., 2018). In addition, when compared to synthetic chemopreventive agents, phytochemicals have limited cytotoxicity and their interplay with different molecular cascades makes them suitable anti-neoplastic agents (Neergheen et al., 2010).

Epidemiological studies have confirmed that the daily consumption of fruits, vegetables, plants, and herbal products can reduce the risk of several chronic diseases, such as diabetes mellitus (DM), cardiovascular (CV), and metabolic diseases, and even cancer (Hussain et al., 2016). Since plant-based products are rich in phytochemicals, their habitual intake improves the health status and prevent diseases (Manach et al., 2009).

Cancer is considered as the deadliest disease all over the globe. Many advance anti-cancer treatments are in the clinical and in pre-clinical trials to conquer the unbeatable fort of carcinogenesis. Natural (heterocyclic moieties) and synthetic products (Vinblastine and vincristine) are also in use as anticancer potential compound and it is believed to reduce the proliferation of the tumor cells, resulting in the increase of patient's survivals (Ali et al., 2015). Nano-based anticancer drugs have gained the spotlight of the world's scientific community, because of its targeted delivery drift. Nano medicines have a potential to deal with cancer even at an early stage with minimum side effects. These side effects can be eradicated by understanding the exact mode of action of these drugs (Ali, 2011). The fusion of metal complexes with thalidomide based Dicarbamate ligand has significant anti-cancer activity against Mcf-7 breast cancer cell lines. Copper, Nickle, and ruthenium ions were processed with ligand, and the resulting compound can be visualized by various spectroscopic techniques. Ligand and its complexes have strong binding affinity with DNA because of its high DNA binding constant ratio (Ali et al., 2013c). It is observed that curcumin ligand coupled with ruthenium ion has less toxicity to erythrocytes than the synthetic heterocyclic drugs currently used. This metal complex along with ligand has potential anticancer activities against HeLa, HepG2, MDA-MB-231, and HT-29 cell lines (Ali et al., 2013b). Imidazole is also reported as an anticancer agent and is not only an alkaloid and aromatic diazole, but also has high anticancer profile, because of its human friendly anticancer mechanism of action (Ali et al., 2017). Platinum compounds are also believed to be significant key player in coming times for the treatment of cancer. Although, these compounds are noted to have certain limitations, but platinum-based co-delivery can reduce these limitations. The third-generation platinum analogs (lobaplatin, heptalotin) are more superior than the second-generation analogs (carboplatin, oxaliplatin, nedaplatin) because of their better anticancer activities (Ali et al., 2013a). Certain drugs such as Salicin, naproxen, and diclofenac etc. are used to reduce the inflammation rate that is caused by cancer. All these anticancer drugs can be determined by certain chromatography techniques such as reverse phase liquid chromatography (RP-HPLC) and micro-HPLC (Sultan et al., 2005).

Berberine is an isoquinoline alkaloid derivative mostly obtained from the roots, stem, bark, and rhizomes of berberis, Phellodendron amurense, Coptis chinesis, and Hydrastis canadensis (Kong et al., 2004; Lee et al., 2012). These plants have been implemented in Chinese medicine for nearly 2,000 years for treating various diseases (Imenshahidi and Hosseinzadeh, 2016). However, the pharmacologically active component of these plants, i.e., berberine has only recently been identified (Imenshahidi and Hosseinzadeh, 2016). Berberine is a potent alkaloid with considerable pharmacological activities, including antimicrobial, antioxidant, anti-inflammatory, antidiabetic, hypoglycemic, hepatoprotective, and chemopreventive properties (Amritpal et al., 2010; Kumar et al., 2015). It is now clinically proven that berberine is a potential treatment for diseases, like diarrhea, ulcers, DM, CV diseases, hypercholesterolemia, fatty liver, polycystic ovary syndrome, and even cancer (Kumar et al., 2015; Imenshahidi and Hosseinzadeh, 2016). Regarding pharmacokinetics, berberine is not easily absorbed in the gut, despite it has been reported that berberine and its active metabolites are found to be higher in tissues as compared to blood following oral administration (Ye et al., 2009). Owing to these features, the delivery of berberine to target tissue site has become seriously challenging.

Berberine is one of the most used natural products Worldwide as more than 25 billion pills of berberine have been reported to used annually in Asia and African countries. It also has few limitations that it may cause intestinal side effects including cramping, stomach upset, and shaping gut microbiota. Pharmacokinetic profile of berberine has been reported in plenty of studies that it has low rate of absorption, especially when taken orally (Zhang et al., 2008; Alolga et al., 2016).

Extreme low absorption rate of bioactive berberine has been one of the biological pitfalls that hinder the use of berberine against multiple chronic disorders and cancer. It is documented that only 0.5% of ingested berberine absorbed in small intestine while this percentage is further decreased, when enter in systemic circulation. Different clinical trials have been noted to use as emulsifier enhancers to uplift the absorption rate of berberine in human to maximize its clinical efficacy. Different FDA approved food additives including TPGS, Quillaja extract etc. have been observed in clinical trials but nano-based formulation is believed to be an ideal candidate to increase absorption percentage as at nano scale level, compounds can absorb rapidly in gut and stability can be controlled via multiple characterization approaches (Sahibzada et al., 2018; Kwon et al., 2020).

Nanotechnological approaches for drug delivery have been put in practice for nearly a decade, with nanoformulations containing berberine appearing as a suitable therapeutic approach for several cancers (Mostafavi et al., 2019). In this sense, the present review presents comprehensive data on berberine chemistry, pharmacology, with special emphasis on its anticancer potential, and lastly provides an up-to-date vision on nanoformulations containing berberine as therapeutic/chemopreventive alternatives for both neoplastic and solid tumors.

Berberine, most specifically isoquinoline alkaloid berberine (Figure 1) is a member of the protoberberine alkaloids family (Kong et al., 2004). The most common member of this family are jatrorrhizine, columbamine, palmatine, coptisine, lambertine, canadine, and others (Grycová et al., 2007; Sun et al., 2009). The major sources of berberine includes barberry (Berberis spp.), meadow rue (Thalictrum spp.), celandine (Chelidonium spp.), goldenseal (Hydrastis spp.), and Phellodendron spp. (Singh and Sharma, 2018). Berberine is mostly isolated by alcoholic extraction (Fata et al., 2006), where following alcoholic extraction, the addition of acetic acid generates berberine chloride, hydrosulphate, and iodide berberine or dihydrodeoxyberberine (Fata et al., 2006).

Protoberberine alkaloids are widely recognized for their antimicrobial, anti-inflammatory, and antioxidant effects (Manske and Holmes, 2014). Specifically, plants belonging to the genus Berberis (barberry) have been implicated to in Japanese traditional medicine to treat cholera and diarrhea (Salehi et al., 2019b), while in Indian folk medicine, it has been used to treat cholera, malaria, and other gastric diseases (Salehi et al., 2019b). Several other reports have also shown that barberry can prevent metrorrhagia, renal bleeding, blood pressure reduction (Belwal et al., 2020), besides to be extensively used for the treatment of gastric disorders (Salehi et al., 2019b). The effects of barberry are mostly connected to the active compounds present in its chemical composition, namely berberine, where modifications of berberine have resulted in the production of several derivatives with efficient pharmacological properties (Table 1).

Berberine has begun to emerge as a potent anticancer agent over the years (Sun et al., 2009; Liu et al., 2019). Berberine has tremendous antioxidant effects, which makes it suitable for the treatment of various diseases, such as DM, diarrhea, hormonal disorders, and so on (Tillhon et al., 2012). However, the pro-apoptotic role of this alkaloid was bleak. Berberine has been reported to inhibit proliferation, metastasis in various cancers, such as leukemia, colorectal, prostate, lung, glioma, and ovarian cancers (Jantova et al., 2007; Chen et al., 2015; Guamán Ortiz et al., 2015; Lu et al., 2016; Tian et al., 2016; Wang et al., 2016), although there are certain hindrances which have greatly affected the tumor inhibitory properties of berberine. The major reason for this limited apoptotic role is its poor absorption and limited bioactivity (Chen et al., 2014). However, with the advancements in the field of nanotechnology these issues can be overcome.

Berberine exerts its apoptotic role in tumor cells via activation of pro-apoptotic genes. Briefly, berberine is able to disrupt the B-cell Lymphoma-2/Bcl-2 associated protein X (Bcl-2/Bax) ratio, which in turn decreases the mitochondrial membrane potential of tumor cells (Li et al., 2017). It also triggers the caspases activation through intrinsic apoptotic pathway, consequently, it activates caspase-3 and−8 which release cytochrome C (Li et al., 2018). In addition, berberine is also an activator and modulator of cell cycle; specifically, it influences the cell cycle activity via inducing cell cycle arrest in tumor cells at the G1 phase. Interestingly, at lower concentrations, berberine inhibits tumor cells growth at G1 phase, while at higher concentrations it triggers growth arrest at G2/M phase of cell cycle (Eo et al., 2015). Moreover, it has been reported that berberine promote Reactive Oxygen Species (ROS) production in tumor cells, ultimately triggering apoptosis. Other studies have reported that the combination of chemotherapy and berberine can reduce the cytotoxic effects of these drugs and improve their therapeutic efficacy, thus, enhancing the therapeutic outcomes in various cancers (Park et al., 2015).

Being a natural compound, berberine has limited cytotoxicity. A number of studies have shed light on the fact that berberine is extremely target-specific and induces apoptosis in tumor cells with limited cytotoxicity on normal cells (Liu et al., 2011; Yang and Huang, 2013). However, the low absorption rate and poor stability are the two major stumbling blocks, which have reduced its cytoprotective efficacy (Liu et al., 2016). Consequently, new approaches toward stabilizing berberine and increasing it absorption have been made. This has led toward the development of novel berberine derivatives with changes at different structural positions, such as the C8, C9, C10, C12, and C13 for improved stability and biological activity (Milata et al., 2019). These modifications have been reported to increase the antimicrobial activity of berberine (Milata et al., 2019), although the change at C9 position has been evidenced to increase the antitumor potential of berberine (Zou et al., 2017). Altogether these findings indicate that berberine is a potentially suitable drug for chemoprevention and therapeutic interventions.

Berberine has been widely used as potential therapeutic agent in Traditional Chinese and herbal medicines to address multiple biological issues, including cancer. In modern medicine, berberine is classified under class III drug as per biopharmaceutical classification system (BCS) due to its poor membrane permeability. In this way, nanotechnology has opened a new avenue for novel development of drug delivery vehicles to improve cancer treatment. Indeed, nanodelivery strategies of anti-cancer drugs have been considered an iron gate for cancer therapy. However, to obtain optimal benefit from this potential biological compound, modern biotechnology have offered different nanoencapsulation approaches, including magnetic nanoparticles, semi-crystalline nanoparticles, phosphor-lipid drug carriers, silver nanoparticles, mitochondrial targeted nanocarrier, alkylated berberine, berberine-loaded liposomes, pH sensitive lipid-base nanocarriers, electrochemical DNA biosensor, chitosan nanoparticles, niosome and lipo-niosome formulations, to enhance berberine delivery and bioavailability in the targeted regions of body. Thus, nanoformulations containing berberine have revealed to be extremely efficient in enhancing berberine stability as well as its oral availability. In the next sub-sections, we discuss in detail the nanotechnology-based therapeutic interventions of berberine and their role in treating cancer.

Many herbal drugs have been used with different combinations to enhance anticancer effect with minimize side effects (Ali et al., 2019b). In vitro analysis was performed by using chloroform extract of clove bud on H1299 and A549 human cancer cell lines to study cellular migration and apoptosis. It was noted that natural compound of clove extract possesses inhibitory effects on cellular migration and induce apoptosis. It is believed that clove bud extract could be significant contributing agent for lung cancer treatment and its effectiveness can be improve by nano-formulation approach to enhance its bioavailability (Ali et al., 2019a).

Berberine is an isoquinoline alkaloid that has been used from thousands of years for multiple health affections. In recent years, the shifting pendulum of therapeutics for naturally-occurring anticancer molecules have been hub of research. Indeed, traditional herbal products, including berberine, berbamine, Ginkgo Biloba, curcumin, quercetin have been reported to have a great impact on tumor metastasis through several pre-clinical and clinical studies (Sithranga Boopathy and Kathiresan, 2010; Cragg and Newman, 2013). Indeed, berberine, as well as many other natural products, may serve as an iron gate for cancer therapy and have shown to be effective against multiple types of cancer, although its limited cell permeability and dissolution rate due to brief plasma half-life have hampered its effective use. Thus, to enhance the anti-metastatic and anti-tumor efficacy of berberine, nanobiotechnology have offered a nano-platform to solve this big trouble by nanodelivery bioformulation approach.

Nanomedicines with unique technological improved version would be the future of pharmaceutics in this rapid changing World. The breakthrough in computational biology and artificial intelligence are believed to play a decisive role to precisely target the culprit cancer causing cells in our biological system. Particle size reduction approach to increase bioavailability of green compounds and the biological activity of soluble nano drug systems are gaining huge acceptance in clinical traits. Currently available data have shown that berberine delivery via nanocarriers in specific cancer sites are reported to upregulate p53, bax, beclin-1, caspases activity, including caspase3/9, MAPK signaling cascade and to downregulate the expression of Bcl-2, mTOR, Wnt/β-catenin. However, despite the berberine bioconjugation and bioformulation with potential agents to enhance its efficacy have emerged as therapeutic demand to step forward to conquer the unbeatable fort of cancer progression, further studies are still needed to support such health effects and upcoming medical applications.

Herbal bioactive compounds are reported to have few pharmacokinetic limitations including poor aqueous solubility, low bioavailability and less effectiveness, low site-specific delivery, and stability concern that demand for novel formulations to overcome disadvantages of natural products. Nanoplatform offers multiple codelivery strategies of berberine with other anti-cancer drugs and to enhance stability of natural compounds by preventing from low pH and metabolic effects in gut that prolong its stability to remain in bloodstream and enhance bioavailability (Mirhadi et al., 2018). Cellular toxicity and unwanted side-effects of targeted nano-herbal formulations is limited by minimizing the toxic level dose. Huge published data from the literature support the non-toxic impact of multiple nanomedicines (Voigt et al., 2014). However few nanomaterials are also reported in the literature to enhance cellular toxicity and oxidative stress including CNT, fullerene, and metal oxide (Bonner, 2007). Such hinderance in the clinical application of nano-nutraceuticals formulations and diagnosis are now resolved by using selective nano-materials for clinical purposes as cerium oxide based nano-materials are reported have anti-oxidant potential an many other magnetic nanoparticles are use in MRI and FMIR diagnosis procedures with no or limited side effects (Dhall and Self, 2018).

Optical and magnetic properties of nano-carriers conjugated with drug and targeted moieties would be suitable candidate to address the toxicity challenges significantly. Hybrid nano-structures are expected to strengthen the application of nanomedicines more effectively in future. Hybrid nanomaterials of unique elements like cerium with multiple oxidation states and pseudo infinite half-life could serve as potential addition in pharmaceutical industry to limit cancer recurrence and metastasis (Xu et al., 2020).

MJ, ZJ, HS, QQ, SR, and JS-R: conceptualization. All authors: validation investigation – data curation writing, read, and approved the final manuscript. ZA, ZJ, CQ, MS, SR, BS, NC-M, AA, and JS-R: review and editing.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.