Triple-negative breast cancer (TNBC) represents the most aggressive variant of breast cancer, characterized by restricted treatment alternatives and dismal prognosis. The anti-tumor efficacy of lupeol against breast cancer cells and the associated processes were investigated by various in vitro and in vivo experiments (Table 2). These research findings suggested that triterpenoids may impede TNBC through many signaling mechanisms. Furthermore, experimental evidence demonstrated that triterpenoids displayed remarkable anti-proliferative and anti-metastatic properties and the capacity to induce autophagy by blocking various signaling pathways, including the Akt-mTOR pathway (Saini et al., 2019). Lupeol isolated from ethanolic extract of Bombax ceiba (stem bark) via normal phase column chromatography. Out of which fourteen derivatives were synthesized and assayed for their antitumor potential against A549, MDA MB-231, and HeLa cells. Amongst all the synthesized derivatives of lupeol, pyrimidine-2(5H)-thione derivative (15) displayed significant growth inhibition in a dose dependent manner in all the selected cancer cells [MDA MB-231 (IC₅₀ 27.13 µM), A549 (IC₅₀ = 46.27 µM), and HeLa (IC₅₀ = 45.95 µM)] (Wu et al., 2023).

Although chemotherapy is still the primary treatment for cancers, issues like poor chemotherapy outcomes and drug resistance susceptibility are present. Natural compounds have various pharmacological potential that are significant sources for drug discovery in tumor treatment. Integrating chemotherapeutic agents with natural substances is becoming recognized as an important technique and developmental trajectory for cancer treatment (Castañeda et al., 2022; Fatma et al., 2024). Fatma et al. (2024) identified 20 trials and proved that Lupeol affects tumor volume and weight. Moreover, Lupeol and other chemotherapeutic drugs (such as cisplatin, oxiplatin, 5-fluorouracil and sorafenib) had superior results compared to their administration in alone or in combination. Lupeol further interacted with multiple signaling molecules and pathways to have an anti-cancer action (Fatma et al., 2024). Another study evaluated the anticancer potential of lupeol, isolated from Elephantopus scaber L. (leaves), and reported significant inhibition of MCF-7 cell viability (IC₅₀ = 80 μM), cell death induction, altered cellular morphology and reduced cancer cell population with no effects on normal cells. Lupeol treatment induced apoptosis via downregulating Bcl-2/Bcl-xL protein expressions in MCF-7 cells in a dose dependent manner (Pitchai et al., 2014). These findings indicated lupeol as a potent anticancer adjuvant in breast cancer management. The anticancer properties of lupeol are attributed to its antiproliferative, antimigrative, and apoptotic effects. Lupeol synergistically increased the antiproliferative effect of doxorubicin on three different cells, including MCF-7 (IC₅₀ = 42.55 μM), MDA-MB-231 (IC₅₀ = 62.24 μM), and HFF (IC₅₀ = 65.9 μM) cells in a dose dependent manner. Lupeol treatment resulted in reduced cell migration induced by doxorubicin. Apoptotic cells were elevated in lupeol and doxorubicin-treated cells with increased caspase-3 activation. This combinatorial therapy reduces MMP-9 expression levels in both MCF-7 and MDA-MB-231 cells in a dose dependent manner (Malekinejad et al., 2022).

A separate in silico investigation suggested that lupeol may impede TNBC by targeting various cellular signaling pathways. Furthermore, experimental results (both in vitro and in vivo) confirmed that lupeol displayed considerable anti-metastatic and autophagy-inducing properties by inhibiting the AKT-mTOR pathway and activating autophagy, suppressing epithelial-mesenchymal transition. This study confirmed the autophagy-inducing capability of lupeol in TNBC cells, suggesting its usage as a dietary supplement or prospective therapeutic alternative for TNBC (Zhang et al., 2022). In patients receiving 5FU, hyperactivation of c-MET and type-A receptor 2 (EphA2) was associated with a decreased risk of disease-free survival. Nevertheless, the invasive and tumorigenic efficacy of TNBC cells was significantly reduced upon silencing both of these genes, suggesting that a dual-target approach is feasible. A synergistic approach utilizing 5FU and Lupeol has shown encouraging anticancer effects in vitro, in vivo, and in ex vivo (patient-derived tumor culture model). Even in the presence of HGF, this synergistic regimen is adequate whichmountc-MET and EphA2 activation. These data provided the basis for the clinical validation of this combinatorial therapeutics for TNBC patients (Mitra et al., 2023).

A supplementary investigation corroborated the utilization of synergistic methods as an innovative strategy to surmount monotherapy resistance in breast cancer treatment. The combination of β-Carotene and lupeol had the most potent inhibition (IC₅₀ = 54.8 μM) compared to the standard inhibitor, whereas β-Carotene (IC₅₀ = 101.5 μM) and lupeol (IC₅₀ = 84.08 μM) exhibited moderate inhibition in a dose dependent manner. The treated animal groups’ hematological, biochemical, and tissue antioxidant markers returned to normal levels. β-carotene and lupeol reduced viable cell count and tumor’s volume and weight and extending the lifespan of EAC tumor-bearing mice (Jana et al., 2023). An extract of Euphorbia fischeriana Steud. was utilized to investigate the inhibitory effects of lupeol on invasion of MDA-MB-231 cells. Lupeol markedly impeded the invasion of MDA-MB-231, as demonstrated in all experimental assays, including wound healing, cell adhesion, and transwell assays. Lupeol suppressed MDA-MB-231 cells migration by downregulating the expression levels of NF-κB, COX-2, p65, MMP-2/9. This investigation confirmed the inhibitory efficacy of lupeol on the nuclear NF-κB signaling pathway in breast cancer in a dose dependent manner (Wang et al., 2016). These investigations may validate the anticancer activity of lupeol, either alone or in combination with other natural or chemotherapeutic agents, and offer compelling evidence for its use as an anti-breast cancer agent.

Lupeol has been insufficiently investigated in cervical and ovarian cancer, hence offering fresh opportunities for future researchers to examine its anticancer potential in these malignancies. In HeLa cells, lupeol administration drastically decreased cell proliferation and viability by triggering S-phase cell cycle growth arrest and reducing the expression of CDKs and S-phase cyclin. Lupeol administration also elevated the expression levels of cyclin-dependent kinase inhibitors, specifically p21 (at both protein and mRNA levels). Additionally, lupeol prompted apoptosis and elevated the expression of apoptotic markers, including cleaved PARP and Bax/Bcl-2 ratio in a dose dependent manner. Additionally, increased mitochondrial superoxide production and decreased healthy mitochondrial mass were seen in HeLa cells treated with lupeol. The findings indicate that lupeol may serve as an efficacious chemotherapeutic treatment for cervical cancer, owing to its growth-inhibitory properties via the activation of S-phase cell cycle growth arrest and death (Prasad et al., 2018). Lupeol suppressed growth and induced apoptosis in ovarian cancer cells via inactivating the PI3K/PKB/mTOR signaling pathway. Lupeol potentially enhanced cell apoptosis, reduced cell viability, triggered G1 phase growth arrest and decreased the ratio of phospho-AKT to PKB and phospho-mTOR to mTOR in a dose dependent manner (Chen and Zhang, 2021).

Gastric cancer is histologically identified using endoscopic biopsy and staged utilizing laparoscopy, CT, PET, and endoscopic ultrasound. The disease exhibits significant molecular and phenotypic heterogeneity (Smyth et al., 2020). The primary intervention for early stomach cancer is endoscopic resection. Unresectable stomach carcinoma is managed with surgical intervention that must encompass D2 lymphadenectomy. Perioperative (or adjuvant chemotherapy) enhances survival in patients with advanced malignancies. Advanced stomach cancer is managed with successive chemotherapy regimens, commencing with a platinum and fluoropyrimidine combination in the first line (survival is under 1 year). Approved targeted therapy for gastric cancer comprises nivolumab, trastuzumab, ramucirumab, and pembrolizumab (Van Cutsem et al., 2016; Hartgrink et al., 2009). Researchers have employed lupeol as a promising lead candidate for treating gastric carcinoma and colorectal and renal cell carcinomas to address these limitations (Table 3). Lupeol showed efficacy against various gastric cancer cell lines (HGC27, BGC823, and N87) by decreasing their proliferation through natural killer cell activity enhancement. Lupeol further elevated IFN-γ, CD107a, and PFP expression levels by activating the PI3K/Akt/Wnt/β-catenin signaling pathway in a dose dependent manner (Wu et al., 2013).

A separate investigation revealed the growth-inhibitory effects of lupeol and stigmasterol, which impeded cell migration and HUVECs morphogenesis. Both drugs markedly diminished the transcript levels of TNF-α, resulting in decreased phosphorylated forms of FAK, Src, PCL, and Akt. In vivo, administration of lupeol and stigmasterol led to diminished development of CCA tumor xenografts and impaired tumor angiogenesis. Both the phytocompounds did not exhibit any significant toxicity in mice. The phytocompounds effectively inhibited CCA tumor growth, targeted tumor endothelial cells via targeting their anti-inflammatory properties, making them promising candidates for treating CCA tumors (Kangsamaksin et al., 2017). Most renal cell carcinoma (RCC) patients exhibit a significant propensity for developing resistance to radiation therapy and chemoresistance. Treatment with lupeol (LC₅₀ = 40 μM) on SK-RC-45 cells for 48 h generated mitochondrial hyperfission, ultimately resulting in apoptosis, while SK-RC-45 countered this effect by promoting autophagy-mediated selective clearance of disintegrated mitochondria in a dose dependent manner. Consequently, lupeol possesses the potential to serve as an effective treatment against renal cell carcinoma through the modification of mitochondrial dynamics (Sinha et al., 2019). Angiogenesis is a defining characteristic in tumor initiation, development, and growth. Luteolin has demonstrated superior efficacy in suppressing angiogenesis in the CAM assay compared to lectin and lupeol. Luteolin showed superior efficacy in preventing HT-29 cell migration. Software analysis has selected the optimal target proteins among these bioactive compounds and VEGF was identified as one of the targets of luteolin (Ambasta et al., 2015).

A separate study examined the growth inhibitory and anti-inflammatory potential of lupeol and diindolylmethane (DIM) on the growth of experimental bladder cancer. Experimental results demonstrated that combinatorial treatment inhibited bladder tumor growth (confirmed by histopathological analysis). Moreover, there was a momentous boost in PTEN expression and a notable decline in expression level of TNF-α, NF-κB (p65), and Cox-2 in bladder tissue samples, as well as in NMP 22 from urine samples. Preventive DIM and lupeol treatment are effective Cox-2 inhibitors, activating PTEN (tumor suppressor protein) in experimental bladder carcinogenesis via growth inhibitory and anti-inflammatory phenomenon in a dose dependent manner (Prabhu et al., 2016).

Lupeol has demonstrated differential expression of Wnt/β-catenin signaling in human CRC (DLD 1 and HCT 116) cells, leading to decreased cell viability, increased apoptotic induction, diminished colonogenic capacity, reduced β-catenin mRNA level, and lowered expression of Wnt target genes in a dose dependent manner. It obstructed cytoplasmic translocation of β-catenin to the nucleus. Significantly, all these efficacies of lupeol were confined to cells with constitutively active Wnt/β-catenin signaling, while few were noted in cells devoid of such signaling. This work also indicated that inhibiting Wnt signaling in cells with constitutively active Wnt/β-catenin diminishes lupeol efficacy, but activating Wnt signaling enhances the cells’ sensitivity to the inhibitory effects of lupeol (Tarapore et al., 2013).

A variety of first-line chemotherapeutic agents have been employed in colorectal cancer treatment. Oxaliplatin (OXA) (alkylating cytotoxic agent) is typically administered with other chemotherapeutic agents to treat advanced stage (II and III) CRC. Cancerous cells frequently develop multidrug resistance, posing significant barrier to cancer therapy. Lupeol-treated CRC cells exhibited diminished cell viability, induced apoptosis, decreased ABCG2 expression, and triggered endoplasmic reticulum stress to provoke oxaliplatin-resistant cell death in a dose dependent manner. Anti-tumor activity of lupeol on OXA-resistant cells surpassed that observed in LoVo parental cells. Moreover, lupeol injections substantially decreased tumor size in a xenograft animal model, acting as a potent sensitizer for chemoresistance and potentially serving as a novel adjuvant therapy for chemoresistant patients (Chen et al., 2018).

Lupeol enhances the sensitivity of drug-resistant cancerous cells to clinically authorized medications. Lupeol, independently or in conjunction with approved medications, suppresses inflammation in several cancerous cells by modulating the expression levels of IFN-γ, IL-6, and TNF-α. Lupeol therapy modulated PI3K/AKT/mTOR signaling pathway and expression levels of caspases, Bcl-2, FAS, BAX, and survivin. It additionally prompted cell death in therapy-resistant cells and influenced many molecules associated with cell cycle regulation, including PCNA, cyclins, p21, CDKs, and p53 across distinct carcinomas. Lupeol enhanced sensitivity of therapy-resistant cancer cells to multiple therapeutically approved medicines by altering distinct signaling pathways associated with chemoresistance. Consequently, Lupeol may serve as an adjuvant compound with clinically approved medications to enhance efficacy and mitigate toxicity. Lupeol chemosensitizes the therapy-resistant cancer cells for the treatment of various clinically approved drugs via modulating expression levels of IL-6, TNF-α, and IFN-γ. Lupeol, via altering expression levels of Survivin, BCL-2, BAX, Caspases, and FAS, and modulating cell signaling pathways induce cell deaths among therapy-resistant cells. Thus, Lupeol might be used as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase the effectiveness (Maurya et al., 2020).

Hepatocellular carcinoma (HCC) is the second foremost cause of cancer-related mortality, and its incidence is rising worldwide. Notwithstanding progress in preventive methods, screening, and innovative technology in diagnosis and treatment, incidence and mortality persist in escalating (Llovet et al., 2022). Cirrhosis remains the significant risk factor for the onset of hepatocellular carcinoma, irrespective of its cause. Accumulating research indicates that specific natural food metabolites may serve as potential sources for preventing and treating liver cancer (Mandlik and Mandlik, 2021). Dietary triterpenoids and their active derivatives have been reported to inhibit the commencement and development of liver cancer through various phenomenon, including protection against liver carcinogens, enhancement of chemotherapeutic efficacy, inhibition of tumor cell growth and metastasis, and reduction of oxidative stress and chronic inflammation (Sureda et al., 2021). A study indicated the anticancer properties of lupeol extracted from Avicennia marina, which thrives in the deserts of the UAE. Lupeol administration exhibited substantial growth-inhibitory effects on MCF-7 and Hep3B cells, including parental and resistant strains. Lupeol markedly reduced BCL-2 gene expression in Hep3B cells (both parental and resistant), resulting in the triggering of apoptosis and activation of executioner caspase-3. Lupeol exhibited no significant impact on monocyte proliferation; however, it increased growth arrest at G1 phase and reduced apoptotic rates of monocytes (after 48 and 72 h), suggesting a lack of immuno-inflammatory responses. Lupeol can be regarded as a promising, effective, and safe anticancer drug, notably against Hep3B cancer cells (Eldohaji et al., 2021).

Lup-20 (29)-en-3b-ol (lupeol) impeded self-renewal capacity of liver tumor-initiating cells found in both HCC cells and clinical hepatocellular carcinoma samples, as evidenced by hepatosphere formation. Moreover, lupeol suppressed tumorigenicity in nude mice and decreased CD133 expression level. Furthermore, lupeol enhanced the sensitivity of HCC cells to chemotherapeutic drugs via PTEN/AKT/ABCG2 pathway. PTEN is essential for self-renewal and chemoresistance of liver tumor-initiating cells; PTEN downregulation by lentiviral method negated impact of lupeol on liver tumor-initiating cells. In chemoresistant HCC tumor model (in vivo), lupeol significantly reduced tumor size of MHCC-LM3 HCC cell line-derived xenografts, with effects comparable to those of combined cisplatin and doxorubicin therapy. Lupeol demonstrated synergistic efficacies without negatively impacting body weight when administered alongside chemotherapy agents. These data indicated that lupeol may be an efficient dietary phytochemical targeting liver T-ICs (Lee et al., 2011). A different group documented the anticancer effectiveness of lupeol against SMMC-7721 cells. Lupeol treatment of SMMC-7721 cells demonstrated reduced proliferation and clonogenic survival when exposed to γ-radiation. It additionally prompted cellular accumulation during the G2/M phase in conjunction with γ-radiation. Consequently, lupeol-sensitized SMMC-7721 cells subjected to γ-radiation to undergo apoptosis and displayed activated apoptotic proteins (PARP and caspase-9). In HCC xenograft model, co-administration of lupeol in conjunction with radiation resulted in notable delay in tumor growth in comparison to either radiation or lupeol administered alone, which was well tolerated (Jin et al., 2015).

Constitutive STAT3 activation has been associated with angiogenesis and proliferation in numerous malignancies, including HCC. Lupeol substantially inhibited the constitutive activation of STAT3 phosphorylation (at tyrosine 705 residue) and the phosphorylation of Src and JAK 1/2. Lupeol therapy significantly elevated the mRNA and SHP-2 protein expression levels. The suppression of SHP-2 negated the inhibitory potential of lupeol on STAT3 activation. Lupeol treatment further reduced the expression levels of other STAT3-regulated genes and inhibited STAT3 binding with VEGF promoter. Furthermore, lupeol strongly inhibited growth of several HCC cells, correlating with marked increase in apoptosis (Siveen et al., 2014). In conjunction with S14161, Lupeol demonstrated a synergistic anticancer impact, leading to the chemosensitization of HCC cells to low doses of lupeol. In HCC model, lupeol and S14161 (S14161, a newly identified PI3-Kinase inhibitor in vitro and in vivo) collaboratively suppressed tumor development while activating the PI3-kinase/AKT pathway, resulting in a tumor progression without adversely affecting body weight in a dose dependent manner. Consequently, combining a PI3-kinase inhibitor with lupeol synergistically enhanced anti-tumor efficacy of lupeol and represented a viable method for hepatocellular carcinoma therapy. Inhibition of PI3K synergistically enhanced the anti-tumor efficacy of lupeol in HCC carcinoma (Liu F. et al., 2013).

A separate study examined the synergistic effects of geraniol and lupeol, revealing substantial antiproliferative and proapoptotic impacts on hepatocarcinoma cell lines (SMMC7721 and HepG2). Combined treatment of geraniol and lupeol led to decreased Bcl-2 expression levels and increased levels of Bax and caspase proteins and genes. Additionally, geraniol and lupeol treatment altered expression levels of both c-Jun NH2-terminal kinase and p38 phosphorylation, indicating their involvement in MAPK signaling, thereby suggesting their potential utility in anti-liver cancer treatment (Shen et al., 2019). A separate group investigated the anti growth potential of lupeol on HCCLM3 cells by PARP breakage and caspase-3 activation. Lupeol-induced apoptosis correlates with diminished protein expression of Ser-9-phosphorylated GSK-3β and brain-derived neurotrophic factor (BDNF) and a concurrent reduction in expression levels of c-Myc, cyclin D1, Akt1, PI3K, and β-catenin mRNAs. Inhibition of BDNF overexpression by lupeol led to diminished p-Akt and PI3K (p110α) protein levels, along with the reactivation of GSK-3β activity in HepG2 cells in a dose dependent manner. Lupeol therapy as well suppressed LiCl-induced activation of the Wnt signaling pathway and demonstrated in vitro anti-invasive action in Huh-7 cells. Lupeol exposure diminishes the elevated expression levels of cyclin D1, β-catenin, and c-Myc proteins induced by LiCl. The results demonstrated that lupeol can decrease HCC cell proliferation by suppressing BDNF production and the phosphorylation of GSK-3β(Ser-9), in conjunction with the inhibition of Wnt and AKT/PI3K signaling pathways (Table 4) (Zhang et al., 2015).

A multidisciplinary approach is required to treat oral cancer since every patient has a different combination of problems that affect their quality of life and chances of survival. Multiple triterpenoids, including lupeol, exhibit anticancer efficacy against various carcinomas including oral, lung, melanoma, prostate and retinoblastoma (Table 5) (MR Patlolla and V Rao, 2012). A study showed that lupeol therapy inhibited colony formation, cell proliferation, and EGFR phosphorylation in NSCLC (Non-small cell lung cancer) cells. Furthermore, lupeol prompted apoptosis by enhancing PARP breakage and chromatin condensation and inducing growth arrest in sub-G1 phase cells. In silico investigations demonstrated that lupeol directly interacted with tyrosine kinase domain of EGFR. Lupeol inhibited transcriptional activation and nuclear translocation of STAT3 while downregulation of STAT3 target genes expression levels. Constitutive STAT3 activation through STAT3 Y705D overexpression inhibited lupeol induced apoptosis, indicating suppression of STAT3 activation facilitated apoptosis induction. The anticancer potential of lupeol was consistently noted in EGFR-TKI-resistant H1975 cells (nonsmoking female with non-small cell lung cancer) (EGFR L858R/T790M). Results of this trial indicated that lupeol was applicable for both EGFR TKI-naive NSCLC and advanced NSCLC exhibiting acquired resistance to EGFR TKIs (Min et al., 2019). In head and neck squamous cell carcinoma lupeol has been identified to trigger apoptosis in various carcinomas via extrinsic mechanism. Lupeol administration enhanced p53-mediated Bax expression and triggered intrinsic apoptotic pathways, as evidenced by cleaved caspase-3. Lupeol induced G1 cell cycle arrest by up-regulating CDKN2A expression, leading to cyclinD1 inhibition in a dose dependent manner. In ex vivo experimentations, lupeol administration resulted in Ki67 expression inhibition, reduction in cell viability, and simultaneous caspase-3 activation. Consequently, lupeol re-sensitized primary HNSCC tumor samples that have clinically progressed during a cisplatin therapy program (Bhattacharyya et al., 2017).

Lupeol (50 mg/kg bw) administered in the buccal pouch of golden syrian hamsters completely prevented oral tumor growth and restored biochemical marker levels after DMBA-induced oral carcinogenesis. Chemopreventive potential of lupeol primarily arises from its antioxidant properties and modulatory efficacies on phase I and II xenobiotic metabolizing enzymes, facilitating excretion of carcinogenic compounds during DMBA-induced carcinogenesis in hamster buccal pouches (Palanimuthu et al., 2012). In nasopharyngeal cancer, Lupeol induced apoptosis, oxidative stress, and ferroptosis while mitigating inflammation through the AMPK/NF-κB pathway and increasing the expression levels of ROS, Bax, MDA and caspase-3. It diminished MMP, Bcl-2, TNF-α, IL-6, IL-1β, and superoxide dismutase expression levels. Furthermore, lupeol facilitated iron secretion and lipid peroxidation, results that were mitigated by the ferroptosis inhibitor (Fer-1). Lupeol markedly increased AMPKα phosphorylation and decreased the levels of p-IκBα and nuclear NF-κB p65. Furthermore, lupeol inhibited carcinogenesis in xenografts inside naked mice (Zhou et al., 2022).

Vasculogenic mimicry (VM), characterized as an endothelial cell-independent alternate pathway for nutrition and blood delivery by dysregulated tumor cells, is linked to unfavorable prognosis in OSCC (Oral Squamous Cell Carcinoma) (Salem and Salo, 2021; Hujanen et al., 2021). In human oral cancer cells, lupeol combined with paclitaxel induced apoptosis and disrupted vasculogenic mimicry-associated behaviors. The efficacy of this innovative interventional method was additionally confirmed in oral cancer patient (derived tumor explant culture model). Tumor model replicated anti vasculogenic mimicry efficacy of combined lupeol and paclitaxel via down-regulating HIF-1α/EphA2/Laminin-5γ2 cascade. These results revealed the molecular basis of hypoxia-induced Laminin-5γ2-driven vascular mimicry creation, underscoring that the lupeol-paclitaxel combination may represent a potential therapeutic approaches for vascular mimicry disruption in human OSCC. In human oral carcinoma, combined treatment of lupeol and paclitaxel impeded hypoxia-induced VM via inhibiting HIF-1α-EphA2-Laminin-5γ2 network (Saha et al., 2023). A separate study demonstrated that lupeol decreased the growth of OSCC cells by triggering apoptosis after 48 h of treatment. Concomitant activation of downstream enzymes (PKB, IκB, AKT, NF-κB), ligand-induced EGFR phosphorylation was partially inhibited. Notably, Lupeol inhibited both mRNA and protein expression levels of COX-2. Lupeol treated primary explants (derived from OSCC tissues) demonstrated a marked reduction in Ki67 proliferation relative to untreated control at 48 h. Thus, lupeol served as a potent inhibitor of EGFR signaling in OSCC, suggesting its potential role in eliciting antitumor effectiveness (Rauth et al., 2016). The evasion of apoptosis is a significant hallmark of rapidly growing tumor cells. The topical administration of 0.5% DMBA thrice weekly (for 14 weeks) in buccal pouches of golden syrian hamsters led to OSCC development. This study observed 100% tumor formation and abnormalities in apoptotic marker expression in hamsters treated alone with DMBA (is a potent carcinogen which is widely employed for studying oral tumorigenesis, leading to the development of oral squamous cell carcinoma). Oral treatment of lupeol (50 mg/kg body weight) entirely inhibited tumor (oral) development, reduced expression of p53 and Bcl-2, and elevated expression levels of Bax and caspases (3 and 9). These investigations demonstrated that lupeol suppressed DMBA-induced oral tumorigenesis through its pro-apoptotic properties in golden syrian hamsters (Manoharan et al., 2012).

Clinical and histological data indicates that melanoma evolves through a series of stages, advancing from benign proliferative lesions to primary melanomas without metastatic evidence, invasive central lesions, and finally to metastases (Herlyn, 1990). Lupeol treated melanoma cells including Mel 928 and Mel 1,241 cells (but not Mel 1,011 cells) led to diminished cell viability, induction of apoptosis, decreased clonogenic capacity, reduced β-catenin transcriptional activity, and lower expression levels of Wnt target genes. It further inhibited cytoplasmic translocation of β-catenin to the nucleus and inhibited Mel 928 tumors formation, but not those produced from Mel 1011, when implanted in athymic nude mice. Reduction in tumor development resulting from Mel 928 correlated with reduced expression levels of osteopontin, c-myc, Ki-67, and cyclin D1 in a dose dependent manner. Consequently, either independently or as an adjunct to existing medicines, lupeol may be formulated as a treatment for human melanomas exhibiting constitutive Wnt/β-catenin signaling (Tarapore et al., 2010a). Malignant melanoma, lethal skin cancer reported globally, with a limited and ineffective range of chemotherapeutic options in the advanced stages of the illness. Lupeol was investigated for its effects on two human malignant melanoma cell lines (A375 and RPMI-7951) demonstrating concentration-dependent and selective cytotoxicity, with estimated IC₅₀ values of 66.59 µM for A375 and 45.54 µM for RPMI-7951. Additionally, it inhibited cell migration, decreased cell confluence, reorganized cytoskeletal components, and induced apoptosis-specific nuclear characteristics in a dose dependent manner. In ovo (treatments or the processes used on developing embryos inside the egg), lupeol inhibited angiogenesis by diminishing neovascularization development (Bociort et al., 2021). Lupeol treated Mel 928 and Mel 1,241 cancer cells led to enhanced activation of caspase 3/7 and diminished the β-catenin/TCF4 transcriptional activity associated with Wnt signaling and its downstream targets, specifically IMP 1 and MITF. It additionally suppressed Wnt signaling activation by diminishing nuclear β-catenin levels. Lupeol therapy displayed a nonsignificant reduction in tumour development in Mel 1011-implanted tumors. In contrast, a notable reduction was seen in expression levels of Wnt targets, MMPs, and TIMPs in Mel 928 tumors derived from lupeol-treated mice, indicating its possible impact on metastatic dissemination in a dose dependent manner (Tarapore et al., 2010b).

Tumor-suppressive effects (both systemic and local injections) of lupeol, derived from Indian lettuce, were assessed in a melanoma-bearing mice model. Mice received a single subcutaneous injection of lupeol or olive oil (solvent control) into the dorsal skin or tumor tissue. Rate of tumour growth in the lupeol-injected group were considerably lower than those in the non-treated (NT) and solvent control groups after 7 days after injection. Lupeol markedly reduced the regions strongly stained for PCNA and Ki-67 in tumor tissues relative to NT and solvent control groups. These data indicated that systemic and local administrations of lupeol inhibited tumor proliferation and induced cell cycle arrest in melanoma-bearing murine model. The data showed that lupeol might be an innovative therapeutic alternative for melanoma patients (Nitta et al., 2013).

Lupeol has shown significant growth inhibitory potential against A427 cancer cells via apoptosis induction. Bax and Bcl-2 expression further confirmed this apoptotic induction in lupeol-treated lung cancer A427 cancer cells. Lupeol triggered ROS generation and MMP dysregulation by inhibiting mTOR/PI3K/AKT signalling pathways (He et al., 2018). A series of new lupeol-3-urea/thiourea compounds were assessed against A549, HepG2, and MCF-7 cancer cells. All compounds exhibited superior anticancer activity compared to the parent Lupeol. Lup-20 (29)-en-3β-yl-piperazinecarboxylate-(2,4-fluorophenyl)urea (IC₅₀ = 3.22 μM) exhibited the most potent anticancer activity against A549 cells, being 10 times more effective than Lupeol. Consequently, lup-20 (29)-en-3β-yl-piperazinecarboxylate-(2,4-fluorophenyl)urea served as a novel lead molecule for the advancement of additional efficacious anticancer agents targeting lung cancer (Xu et al., 2024). A separate study investigated the anticancer efficacy of lupeol on A549 and glioma C6 cells. Lupeol significantly diminished cell viability in both cancer cell lines (A549 and C6), indicating its selective anticancer action against these cell lines (Ertorun et al., 2024). The ERK pathway is a critical mechanism in the spread of lung cancer. Targeting this route is crucial in lung cancer research. A separate study revealed, for the first time, strong and specific anti-metastatic effects of lupeol on A549 cells through disruptions in the ERK signaling pathway. Lupeol effectively targeted ERK and MEK proteins, impeded cell migration, and reduced pErk1/2 and epithelial-mesenchymal transition gene expression. Consequently, it may be a prospective inhibitor of the ERK pathway in lung cancer treatment (Bhatt et al., 2021).

Androgen deprivation therapy is frequently employed in prostate cancer management (Schröder et al., 2012). Enzalutamide is a novel androgen receptor inhibitor used for castration-resistant prostate cancer treatment. Toxicity generated by enzalutamide and the potential mitigation of this toxicity was assessed using lupeol. Numerous in vitro and in vivo experimentations demonstrated that lupeol and enzalutamide engage with DNA via electrostatic interactions. Enzalutamide (5–20 μM) induced cytotoxicity in both cancerous (LNCaP and 22Rv1) and standard (PNT2) cells. Nonetheless, Lupeol (10–50 μM) selectively eliminated only cancerous cells. Lupeol mitigated enzalutamide-induced cytotoxicity and genotoxicity in normal cells while significantly inducing cytotoxicity in transformed cells in a dose dependent manner. Lupeol (40 mg/kg) facilitated mitigating oxidative and DNA damage from enzalutamide (10 mg/kg). Lupeol mitigated the hepatic and renal injuries generated by enzalutamide. Consequently, lupeol may serve as an adjuvant to minimize the adverse effects and augment the efficacy of Enzalutamide (Schmidt et al., 2021). In human retinoblastoma (WERI-Rb-1 and Y-79) cells, lupeol diminished cell viability and triggered apoptosis, evidenced by elevated Bax levels and reduced Bcl-2, Ki67, and survivin levels. Moreover, lupeol inhibited spheroid formation and stem-like characteristics of retinoblastoma cells. Furthermore, the ratio of LC3II/LC3I and the levels of Beclin1 &ATG7 were elevated following lupeol administration, suggesting that lupeol may stimulate autophagy in retinoblastoma cells. Inhibitory potential of lupeol on PI3K/PKB/mTOR pathway was subsequently found. Lupeol inhibited tumor growth in tumor-bearing mice, potentially due to its involvement in cell apoptosis, autophagy, and stem-like characteristics (Khan et al., 2023).