Agustine Nengsih Fauzi

Cancer and diabetes represent a dual health burden linked by shared metabolic disturbances, particularly hyperglycemia and glycolytic reprogramming. This metabolic overlap highlights the need for agents capable of modulating both conditions simultaneously. Terpenoids have emerged as promising candidates, and this review synthesizes evidence on six representative compounds—beta‐caryophyllene, carvacrol, zerumbone, limonene, beta‐elemene, and thymol—demonstrating their ability to lower blood glucose levels (anti‐hyperglycemic) and suppress tumor metabolism (anti‐glycolytic). Among these, zerumbone, beta‐caryophyllene, and carvacrol consistently show the strongest dual activity by targeting the phosphoinositide 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), glucose transporter 4 (GLUT4), and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. By contrast, limonene, beta‐elemene, and thymol exhibit asymmetric evidence, with stronger activity in either diabetes or cancer models. To translate these biological effects into clinical outcomes, nanocarrier formulations are required to overcome inherent pharmacokinetic barriers. Furthermore, the synergistic potential of these terpenoids when combined with conventional agents such as metformin and cisplatin underscores a significant translational opportunity to improve efficacy while reducing systemic toxicity. Ultimately, by targeting the shared PI3K/AKT/mTOR axis, these dual‐function agents restore glucose homeostasis while suppressing tumor glycolysis. This integrated mechanistic approach supports a promising, yet underexplored, combination therapy strategy that warrants further translational investigation.

Estrogen receptor‐positive (ER+) breast cancer accounts for the majority of breast cancer cases worldwide, yet the long‐term efficacy of endocrine therapy is limited by resistance and recurrence. While tumor‐intrinsic mechanisms of endocrine resistance are well established, growing evidence highlights the contributions of innate immune cells and the tumor microenvironment (TME) in shaping therapeutic outcomes. This review synthesizes recent advances into how tumor‐associated macrophages (TAMs), natural killer (NK) cells, myeloid‐derived suppressor cells (MDSCs), and tumor‐associated neutrophils (TANs) collectively foster an immunosuppressive TME that undermines endocrine responsiveness. Central to this crosstalk is the STAT3 signaling pathway, which integrates inflammatory and metabolic stress signals to drive immune reprogramming, promotes tumor progression, and facilitates therapy resistance. By activating tolerogenic pathways and inhibiting anti‐tumor immunity, STAT3 provides a mechanistic link between innate immune dysregulation and endocrine resistance. Preclinical studies demonstrate that STAT3 inhibition can restore tamoxifen sensitivity in resistant ER ⁺ breast cancer models, highlighting its therapeutic potential. These insights reveal the immunological complexity of endocrine resistance and provide rationale for combinatorial strategies integrating endocrine therapy with immunomodulation. Future approaches that incorporate STAT3 inhibitor, immune checkpoint blockade, and biomarker‐guided patient selection may transform the management of ER+ breast cancer, offering more durable and clinically meaningful outcomes by acknowledging the emerging interactions between immune dysregulation and metabolic stress in resistant ER+ breast cancer.

Background Triple-negative breast cancer (TNBC) remains a major therapeutic challenge due to the lack of established molecular targets and the presence of highly infiltrating tumor-associated macrophages (TAMs), particularly the immunosuppressive M2 phenotype that drives tumor progression. This study investigated the potential of lutein, a plant-derived carotenoid with anticancer properties, to repolarize human monocyte-derived M2 macrophages into the antitumor M1 phenotype and thereby modulate the TNBC tumor microenvironment. Methods and results CD14 + monocytes isolated from peripheral blood mononuclear cells were differentiated into M1 or M2 macrophages using GM-CSF/IFN-γ/lipopolysaccharide or M-CSF/IL-4, respectively. Lutein’s effects on macrophage polarization, cell proliferation, cell migration and cytokine secretion were evaluated using flow cytometry, MTT proliferation assays, migration assays and enzyme-linked immunosorbent assays (ELISAs) in MDA-MB-231 cells. Additionally, tumor-related protein expressions from MDA-MB-231 cells were analyzed using protein arrays. Lutein significantly reduced the proliferation and migration of MDA-MB-231 cells when co-cultured with M1/M2 macrophages compared to the untreated group. IL-4 stimulation increased the expression of M2 macrophage marker (CD206) and protumor cytokines (IL-10 and TGF-β1), but lutein effectively reduced these elevated molecules in IL-4-activated macrophages. Proteomic profiling revealed that lutein downregulated several protumor proteins (survivin, VEGF, BCL-X, M-CSF, MMP-9) and upregulated antitumor markers (FKHR and GM-CSF). Furthermore, lutein markedly reduced the secretion of proinflammatory and protumorigenic cytokines and chemokines (IL-6, IL-18BPa, CCL2, CCL8, CCL7, CCL3, CCL20, and CXCL8). Conclusion These findings suggest that lutein reprograms M2 macrophages toward an M1-like phenotype and disrupts tumor-promoting signaling within the TNBC microenvironment, highlighting its potential as an adjunct therapeutic agent.

Cancer incidence has increased globally and has become the leading cause of death in the majority of countries. Many cancers have altered energy metabolism pathways, such as increased glucose uptake and glycolysis, as well as decreased oxidative phosphorylation. This is known as the Warburg effect, where cancer cells become more reliant on glucose to generate energy and produce lactate as an end product, even when oxygen is present. These are attributed to the overexpression of key glycolytic enzymes, glucose transporters, and related signaling pathways that occur in cancer cells. Therefore, overcoming metabolic alterations in cancer cells has recently become a target for therapeutic approaches. Natural products have played a key role in drug discovery, especially for cancer and infectious diseases. In this review, we are going to focus on terpenoids, which are gradually gaining popularity among drug researchers due to their reported anti‐cancer effects via cell cycle arrest, induction of apoptosis, reduction of proliferation, and metastasis. This review summarizes the potential of 13 terpenoid compounds as anti‐glycolytic inhibitors in different cancer models, primarily by inhibiting the glucose uptake and the generation of lactate, as well as by downregulating enzymes associated to glycolysis. As a conclusion, disruption of cancer cell glycolysis may be responsible for the anti‐cancer activity of terpenoids.

An active fraction of S. crispus, F3, and its bioactive compounds (lutein, β-sitosterol, and stigmasterol) were reported to have anti-glycolytic activities in MDA-MB-231 cells. Since glycolysis can also regulate metastatic activities in cancer cells, this study investigated the mechanism underlying the anti-glycolytic and anti-metastatic activities induced by F3 and its bioactive compounds on MDA-MB-231 cells. The cells were treated with IC₅₀ concentrations of F3, lutein, β-sitosterol, and stigmasterol. GLUT1 protein expression and localization were then observed using a fluorescence microscope. We found that F3, lutein, and β-sitosterol inhibit localization of GLUT1 to the cell membrane, which causes the decrease in glucose uptake. This is supported by a reduction in PKC activity, measured using a spectrophotometer, and increased TXNIP protein expression detected by Western blotting. Both TXNIP and PKC are involved in GLUT1 activation and localization. The expression of signaling proteins involved in the PI3K/AKT pathway was also measured using a flow cytometer. Results show that F3, lutein, β-sitosterol, and stigmasterol reduced the expression of AKT, pAKT, mTOR, and HIF1α in MDA-MB-231 cells. Transwell migration assay was used to measure migration of the MDA-MB-231 cells. A reduction in fibronectin protein expression was observed by fluorescence microscopy, after treatments with F3 and its bioactive compounds, leading to a reduction in the MDA-MB-231 cells’ migratory abilities. As a conclusion, F3 acts as a metabolic inhibitor by inhibiting metabolic rewiring in the promotion of cancer metastasis, potentially due to the presence of its bioactive compounds.

Background: Survival and progression of cancer cells are highly dependent on aerobic glycolysis. Strobilanthes crispus has been shown to have promising anticancer effects on breast cancer cells. The involvement of the glycolysis pathway in producing these effects is unconfirmed, thus further investigation is required to elucidate this phenomenon.Objective: This study aims to determine the effect of S. crispus active fraction (F3) and its bioactive components on glycolysis in triple-negative breast cancer cells (MDA-MB-231).Methods: This study utilizes F3, lutein, β-sitosterol, and stigmasterol to be administered in MDA-MB-231 cells for measurement of antiglycolytic activities through cell poliferation, glucose uptake, and lactate concentration assays. Cell proliferation was assessed by MTT assay of MDA-MB-231 cells after treatment with F3 and its bioactive components lutein, β-sitosterol, and stigmasterol. The IC50 value in each compound was determined by MTT assay to be used in subsequent assays. The determination of glucose uptake activity and lactate concentration were quantified using fluorescence spectrophotometry.Results: Antiproliferative activities were observed for F3 and its bioactive components, with IC50 values of 100 μg/mL (F3), 20 μM (lutein), 25 μM (β-sitosterol), and 90 μM (stigmasterol) in MDA-MB-231 cells at 48 h. The percentage of glucose uptake and lactate concentration in MDA-MB-231 cells treated with F3, lutein, or β sitosterol were significantly lower than those observed in the untreated cells in a time-dependent manner. However, treatment with stigmasterol decreased the concentration of lactate without affecting the glucose uptake in MDA-MB-231 cells.Conclusion: The antiglycolytic activities of F3 on MDA-MB-231 cells are attributed to its bioactive components.

Pancreatic cancer is an aggressive disease that progresses in a relatively symptom-free manner; thus, is difficult to detect and treat. Essential oil is reported to exhibit pharmacological properties, besides its common and well-known function as aromatherapy. Therefore, this study herein aimed to investigate the anti-proliferative effect of essential oil extracted from leaves of Garcinia atroviridis (EO-L) against PANC-1 human pancreatic cancer cell line. The cell growth inhibitory concentration at 50% (IC₅₀) and selective index (SI) values of EO-L analyses were determined as 78 µg/mL and 1.23, respectively. Combination index (CI) analysis revealed moderate synergism (CI values of 0.36 to 0.75) between EO-L and 2 deoxy-d-glucose (2-DG) treatments. The treatments of PANC-1 cells with EO-L, 2-DG and EOL+2DG showed evidence of depolarization of mitochondrial membrane potential, cell growth arrest and apoptosis. The molecular mechanism causing the anti-proliferative effect between EO-L and 2-DG is potentially through pronounced up-regulation of P53 (4.40-fold), HIF1α (1.92-fold), HK2 (2.88-fold) and down-regulation of CYP3A5 (0.11-fold), as supported by quantitative mRNA expression analysis. Collectively, the current data suggest that the combination of two anti-proliferative agents, EO-L and 2-DG, can potentially be explored as therapeutic treatments and as potentiating agents to conventional therapy against human pancreatic cancer.

Objective: The persistent activation of aerobic glycolysis in cancer cells results in accumulation of lactate and other metabolic intermediates that contribute to tumorigenesis. Increased glycolysis is frequently dysregulated in triple-negative breast cancer (TNBC), which promotes tumor growth and immune escape. This study was conducted to investigate the effect of 2-methoxy-1, 4-naphthoquinone (MNQ), compound extracted from Impatiens balsamina on glycolytic activities in human breast adenocarcinoma, MDA-MB-231 cells. Methods: Initially, MTT proliferation assay was used to test the cell viability with various doses of MNQ (5-100 µM). As the half maximal inhibitory concentration (IC50) was obtained, glucose uptake and lactate assays of the cells were tested with IC50 dose of MNQ. The treated cells were also subjected to gene and protein analysis of glycolysis-related molecules (GLUT1 and Akt). Results: The results showed that MNQ decreased the percentage of MDA-MB-231 cell viability in a dose-dependent manner with the IC50 value of 29 µM. The percentage of glucose uptake into the cells and lactate production decreased significantly after treatment with MNQ as compared to untreated cells. Remarkably, the expressions of GLUT1 and Akt molecules decreased in MNQ-treated cells, suggesting that the inhibition of glycolysis by MNQ is GLUT1-dependent and possibly mediated by the Akt signaling pathway. Conclusion: Our findings indicate the ability of MNQ to inhibit the glycolytic activities as well as glycolysis-related molecules in MDA-MB-231 cells, suggesting the potential of MNQ to be further developed as an effective anticancer agent against TNBC cells.

Studies on green biosynthesis of newly engineered nanoparticles for their prominent medicinal applications are being the torch‐bearing concerns of the state‐of‐the‐art research strategies. In this concern, we have engineered the biosynthesized Luffa acutangula silver nanoparticles of flavonoid O‐glycosides in the anisotropic form isolated from aqueous leave extracts of Luffa acutangula, a popular traditional and ayurvedic plant in south‐east Asian countries. These were structurally confirmed by Ultraviolet‐visible (UV‐Vis), Fourier transform infrared spectroscopy accessed with attenuated total reflection (FTIR‐ATR) spectral analyses followed by the scanning electron microscopic (SEM) and the X‐ray diffraction (XRD) crystallographic studies and found them with the face‐centered cubic (fcc) structure. Medicinally, we have explored their significant antioxidant (DPPH and ABTS assays), antibacterial (disc diffusion assay on E. coli, S. aureus, B. subtilis, S. fecilis, and S. boydii), and anticancer (MTT assay on MCF‐7, MDA‐MB‐231, U87, and DBTRG cell lines) potentialities which augmented the present investigation. The molecular docking analysis of title compounds against 3NM8 (DPPH) and 1DNU (ABTS) proteins for antioxidant activity; 5FGK (Gram‐Positive Bacteria) and 1AB4 (Gram‐Negative Bacteria) proteins for antibacterial activity; and 4GBD (MCF‐7), 5FI2 (MDA‐MB‐231), 1D5R (U87), and 5TIJ (DBTRG) proteins for anticancer activity has affirmed the promising ligand‐protein binding interactions among the hydroxy groups of the title compounds and aspartic acid of the concerned enzymatic proteins. The binding energy varying from ‐9.1645 to ‐7.7955 for Cosmosioside (1, Apigenin‐7‐glucoside) and from ‐9.2690 to ‐7.8306 for Cynaroside (2, Luteolin‐7‐glucoside) implies the isolated compounds as potential bioactive compounds. In addition, the performed studies like QSAR, ADMET, bioactivity properties, drug scores, and toxicity risks confirmed them as potential drug candidates and aspartic acid receptor antagonists. This research auxiliary augmented the existing array of phytological nanomedicines with new drug candidates that are credible with multiple bioactivities.

Tualanghoney (TH) is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM),in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-)responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.