Synergistic Combination Research Articles

From defense to offense: antimicrobial peptides as promising therapeutics for cancer.

Antimicrobial peptides (AMPs), naturally occurring components of innate immunity, are emerging as a promising new class of anticancer agents. This review explores the potential of AMPs as a novel class of anticancer agents. AMPs, naturally occurring peptides with broad-spectrum antimicrobial activity, exhibit several characteristics that make them attractive candidates for cancer therapy, including selectivity for cancer cells, broad-spectrum activity, and immunomodulatory effects. Analysis of a dataset of AMPs with anticancer activity reveals that their effectiveness is influenced by various structural properties, including net charge, length, Boman index, and hydrophobicity. These properties contribute to their ability to target and disrupt cancer cell membranes, interfere with intracellular processes, and modulate the immune response. The review highlights the promising potential of AMPs as a new frontier in cancer treatment, offering hope for more effective and less toxic therapies. AMPs demonstrate promising potential in cancer therapy through multiple mechanisms, including direct cytotoxicity, immune response modulation, and targeting of the tumor microenvironment, as evidenced by extensive preclinical studies in animal models showing tumor regression, metastasis inhibition, and improved survival rates. AMPs show significant potential as cancer therapeutics through their direct cytotoxicity, immune response modulation, and tumor microenvironment targeting, with promising results from preclinical studies and early-phase clinical trials. Future research should focus on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies to fully realize their potential as effective cancer treatments, while addressing challenges related to stability, delivery, and potential toxicity.

Zidovudine in synergistic combination with nitrofurantoin or omadacycline: in vitro and in murine urinary tract or lung infection evaluation against multidrug-resistant Klebsiella pneumoniae.

Limited treatment options and multidrug-resistant (MDR) Klebsiella pneumoniae present a significant therapeutic challenge, underscoring the need for novel approaches. Drug repurposing is a promising tool for augmenting the activity of many antibiotics. This study aimed to identify novel synergistic drug combinations against K. pneumoniae based on drug repurposing. We used the clinically isolated GN 172867 MDR strain of K. pneumoniae to determine the reversal resistance activity of zidovudine (AZT). The combined effects of AZT and various antibiotics, including nitrofurantoin (NIT) and omadacycline (OMC), were examined using the checkerboard method, growth curves, and crystal violet assays to assess biofilms. An in vitro combination activity testing was carried out in 12 isolates of K. pneumoniae. In vivo murine urinary tract and lung infection models were used to evaluate the therapeutic effects of AZT + NIT and AZT + OMC, respectively. The fractional inhibitory concentration index and growth curve demonstrated that AZT synergized with NIT or OMC against K. pneumoniae strains. In addition, AZT + NIT inhibited biofilm formation and cleared mature biofilms. In vivo, compared with untreated GN 172867-infected mice, AZT + NIT and AZT + OMC treatment decreased colony counts in multiple tissues (P < 0.05) and pathological scores in the bladder and kidneys (P < 0.05) and increased the survival rate by 60% (P < 0.05). This study evaluated the combination of AZT and antibiotics to treat drug-resistant K. pneumoniae infections and found novel drug combinations for the treatment of acute urinary tract infections. These findings suggest that AZT may exert significant anti-resistance activity.

Synergistic invitro antimicrobial activity of polyherbal combination of Morinda lucida fruit and Pterocarpus santalinoides seed against multi-drug resistant clinical bacterial isolates

Background: Synergistic drug combination has been shown to be a way of bypassing drug resistance and reducing the amounts of antimicrobials consumed. As infections caused by multi-drug resistant organisms (MDROs) continue to pose global threat, it is important to search for new antimicrobial combinations of plant origin that are safe and readily available. The objective of this study is to evaluate the synergistic antimicrobial activity of extracts of Morinda lucida fruit and Pterocarpus santalinoides seed against multi-drug resistant (MDR) bacterial isolates Methodology: Morinda lucida and P. santalinoides fruits were plucked and washed clean, and the fruits of P. santalinoides were deseeded to remove the seeds. They were cut into smaller pieces and dried under shade before being milled into smooth powder and extracted with methanol. The clinical bacterial isolates used were MDR Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. The phytochemical constituents of the extracts were determined using the standard method. The invitro antimicrobial assay of the extracts was done at a concentration of 50 to 400 mg/ml using the agar well diffusion technique. The minimum inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) of each extract were determined using the Checker-board micro-titration method, and the FIC result obtained for each isolate was used to calculate the fractional inhibitory concentration index (FICI) of the combined extracts. The time kill assay was performed to confirm the synergistic and bactericidal activities from the MIC values obtained. Results: The phytochemical analysis revealed that the extracts of both herbal plants contained alkaloids, phenol, tannin, saponin, glycosides, and terpenoids. The antimicrobial assay results showed that the polyherbal combination of the extracts was active against all the MDR bacterial isolates tested with varying zones of inhibition. The mean inhibition zone diameters of individual M. lucida and P. santalinoides ranged from 18.0±0.9mm to 26.0±1.4mm and 17.0±0.1mm to 24.0±0.2mm respectively, while the MIC ranged from 6.25mg/ml to 12.5mg/ml for M. lucida and 12.5 mg/ml for P. santalinoides. The mean inhibition zone diameter of the polyherbal combination of the two plant extracts ranged from 25.00±00mm to 34.0±0.4mm, which compared favorably with that of levofloxacin control (28.0±0.0mm to 32.00±0.0mm), while their MIC ranged from 0.39mg/ml to 1.56mg/ml. The FIC of M. lucida extract ranged from 0.06mg/ml to 0.25mg/ml while that of P. santalinoides ranged from 0.03mg/ml to 0.13mg/ml. The FICI of combined extracts ranged from 0.09mg/ml to 0.38 mg/ml for all the MDR isolates, which is less than 0.5mg/ml, indicating synergism against all the isolates. The time of kill assay confirmed the synergistic and bactericidal activities with a 3log10 CFU/ml decrease in the number of viable cells within 6 hours of incubation.Conclusion: Our findings showed synergistic antibacterial actions of extracts of M. lucida fruit and P. santalinoides seed against MDR clinical bacterial isolates, comparable to levofloxacin. Combination of these herbal plants may serve as alternative sources of antimicrobial agents for the treatment of infections caused by MDR bacterial pathogens.

Structural studies and functional validation of Eugenol and Ferulic acid against Enterococcus faecalis Sortase A.

Enterococcus faecalis (E. faecalis) is commonly occurring pathogen associated with nosocomial infections. Infections are difficult to treat because of their multidrug-resistant (MDR) nature and their tendency to form biofilms. Therefore, it is essential to find alternative medicinal approaches of treatment. In this regard, targeting an important protein for drug development can be an alternative approach. Sortase A (SrtA) is an important enzyme involved in anchoring cell surface-exposed proteins to the cell envelope. SrtA is present in Gram-positive bacteria which catalyses the attachment of several virulence factors and other proteins to the cell membrane. It is involved in bacterial pathogenesis, therefore, it's a promising drug target for the development of anti-microbial drugs targeting cell adhesion, evasion, and biofilm development.To identify SrtA potential inhibitors, we havepurified E. faecalis Sortase A (EfSrtAΔN59). Structural studiesalong with molecular docking of protein with selected ligand molecules were done andconfirmed by MD simulation experiments. We have also performed functional validation of these compounds on bacterial growth, anti-biofilm assays and inhibition assay of selected ligands were also done against E. faecalis individually and in synergistic combinations. Results indicated that both Eugenol and Ferulic acid bind to EfSrtAΔN59 with significant interactions and show promising results.

Electrochemical detection of human papillomavirus DNA based on an ultrasensitive electrochemical sensing platform using N-graphene paper

Human papillomavirus (HPV) is the primary cause of cervical cancer, a major global health concern affecting women worldwide. Early detection of high-risk HPV genotypes is crucial for timely intervention and reducing disease burden. However, current detection methods often lack sensitivity, speed, or cost-effectiveness, especially in resource-limited settings. This work addresses this critical need by developing an ultrasensitive electrochemical biosensing platform based on nitrogen-doped graphene paper electrodes for quantifying high-risk HPV16 DNA sequences. The N-graphene nanohybrid, fabricated via simple solvothermal treatment of biomass-derived graphene oxide, demonstrated significantly enhanced electrical and electrocatalytic properties compared to undoped graphene. DNA detection was achieved through characteristic oxidation signals of guanine bases, which displayed a wide linear dynamic range (0.5–100 μg/mL), low detection limit (75 pg/mL), and excellent reproducibility (relative standard deviation <3.5 %). Detailed spectroscopic and electrochemical analyses revealed the key roles of pyridinic nitrogen defects in improving interfacial charge transfer kinetics and mitigating biofouling issues. This synergistic combination of high electrical conductivity and versatile surface functionality paves the way for equipment-free, point-of-care genosensor devices tailored for quantitative biomarker screening in resource-constrained environments.

Modification of gel properties of Meretrix meretrix (clam) with polysaccharides: physical characterization and interaction mechanism.

This study investigated the contribution of 11 polysaccharides (2%, w/w), including pectin (PC), κ-carrageenan (KC), ι-carrageenan (IC), gellan gum (GG), guar gum (GM), sodium alginate (SA), konjac gum (KG), gum arabic (GA), fucoidan (FC), locust bean gum (LBG), and curdlan (CD), to the gel and microstructural properties of Meretrix meretrix clam gel (MMG). The hardness, springiness and chewiness of MMG with KC, IC, GG, SA and FC addition increased by ~10%-250%, while PC, GM, KG and LBG groups decreased by ~0.6% to 69%. KC, IC, SA, GG and FC decreased the cooking loss rate (CLR) by 69.4% to 88.7% and correspondingly enhanced the water holding capacity (WHC) by 10.2% to 21.4%, which was accompanied by an increased bound water and immobilized water area and high hydrogen proton density. The addition of KC transformed the MMG microstructure from a loose network with large pores to a compact, dense network, reducing lacunarity by 57.9%. The primary intermolecular forces in MMG with the incorporation of KC, IC, GG, SA and FC were hydrophobic interactions and disulfide bonds, which increased by 32.8%-105.3% and 45.6%-114.5% than MMG alone, respectively. Collectively, KC, IC, GG, SA and FC could improve the gel properties of MMG and the strongest synergistic combination was found in the MMG/KC system. This study suggests that the incorporation of polysaccharides is a strategy with potential for modifying the gel properties of shellfish surimi products. © 2024 Society of Chemical Industry.

Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment.

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment

AbstractCholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti‐tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol‐altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

Sensitization of melanoma cells to standard chemotherapy: G-quadruplex binders as synergistic agents.

The use of chemotherapeutics has achieved considerable success in cancer therapy; however, their toxicity can severely impact patients' health. In this study, aiming to reduce the doses and potential side effects of traditional chemotherapeutics, we systematically treated A375MM human melanoma cells with seven clinically approved antineoplastic drugs, in combination with three well-characterized G-quadruplex (G4) ligands, using either simultaneous or sequential dosing schedules. Interestingly, the G4binders synergized with most of the investigated anticancer drugs, with the degree of synergism being strictly dependent on both the treatment schedule and the drug sequence employed. Notably, some of the synergistic combinations showed selective toxicity towardmelanoma cells over nontumorigenic human keratinocytes. Furthermore, immunofluorescence experiments highlighted the potential implication of G4 structures in the molecular mechanisms driving the synergistic interaction between some chemotherapeutics and G4 binders. Overall, our systematic study supports the combination of G4-interacting molecules with standard antineoplastic drugs as a promising antitumor strategy.

The Application of Nano Zero-Valent Iron in Synergy with White Rot Fungi in Environmental Pollution Control.

Developing efficient and sustainable pollution control technologies has become a research priority in the context of escalating global environmental pollution. Nano zero-valent iron (nZVI), with its high specific surface area and strong reducing power, demonstrates remarkable performance in pollutant removal. Still, its application is limited by issues such as oxidation, passivation, and particle aggregation. White rot fungi (WRF) possess a unique enzyme system that enables them to degrade a wide range of pollutants effectively, yet they face challenges such as long degradation cycles and low degradation efficiency. Despite the significant role of nZVI in pollutant remediation, most contaminated sites still rely on microbial remediation as a concurrent or ultimate treatment method to achieve remediation goals. The synergistic combination of nZVI and WRF can leverage their respective advantages, thereby enhancing pollution control efficiency. This paper reviews the mechanisms, advantages, and disadvantages of nZVI and WRF in pollution control, lists application examples, and discusses their synergistic application in pollution control, highlighting their potential in pollutant remediation and providing new insights for combined pollutant treatment. However, research on the combined use of nZVI and WRF for pollutant remediation is still relatively scarce, necessitating a deeper understanding of their synergistic potential and further exploration of their cooperative interactions.

Enhancing CAR-T cell therapy against solid tumor by drug-free triboelectric immunotherapy

Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35 μA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9 %), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60 % of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.

Enhancing the strength-ductility synergy of dual-phase Al0.3CoCrFeNiTi0.3 high-entropy alloys through the regulation of B2 phase content

In this study, Al0.3CoCrFeNiTi0.3 high-entropy alloys (HEAs) with different phase contents and microstructures were prepared through cold rolling and recrystallization annealing. This method achieved a synergistic combination of strength and ductility, with the CR1000-1 HEA attaining an ultimate tensile strength of 1175 MPa and a uniform elongation of 21.5 %. In Al0.3CoCrFeNiTi0.3, there exist two distinct phase morphologies: dispersed structure and clustered structure. Using in-situ high-resolution digital image correlation at the microscale, it was observed that local strain in the dispersed structure tends to concentrate along the phase boundaries when a small strain is applied. As the applied strain increases, strain rapidly concentrates in the FCC phase and subsequently in the B2 phase. For the clustered structure, the strain initially concentrates rapidly within the B2 phase and then gradually diffuses into the FCC phase. The low degree of inhomogeneity of the dispersed structure reduces the likelihood of stress concentration and the risk of damage initiation. Furthermore, we observed the synergistic strain hardening effect produced by various deformation mechanisms, such as dislocation pile-ups, dislocation networks, interacting stacking faults, and deformation twins. This study provides valuable insights for the fabrication of dual-phase HEAs with enhanced strength-ductility synergy, applicable to a wide range of engineering applications.

Lightweight composite from graphene-coated hollow glass microspheres for microwave absorption

In developing the effective and lightweight materials for microwave absorption, graphene holds a bright promise because of its excellent electrical properties and low density, but it suffers from poor impedance matching; while the hollow glass microspheres on the other hand have extremely low density and are dielectric. Their synergistic combination could achieve a perfect impedance matching and thus create a novel lightweight absorption composite. The metamaterial structure absorber can efficiently absorb electromagnetic waves over a wide frequency range. This study employs a hydrothermal method to deposit graphene onto the surfaces of hollow glass microspheres, followed by the design of a metamaterial absorber. Upon coating with graphene flakes, the composite material effectively dissipates electromagnetic wave energy through mechanisms such as interfacial polarization, dielectric loss, and the multiple scattering effects of hollow glass microspheres and graphene flakes. The composite exhibits an effective absorption bandwidth up to 4.02 GHz under a graphene flakes mass fraction of 30 %. More importantly, the incorporation of the metamaterial absorber design further significantly enhances the absorption bandwidth to 7.7 GHz. This material demonstrates significant advantages in terms of lightweight and broadband absorption performance, providing new insights for the research of high-performance lightweight and wideband absorbing materials in the future. However, further investigation is required to examine its long-term stability and performance in complex environments.

Synergistic effect of SGO/Nickel cobalt sulfide nanocomposite on Ni-foam for supercapacitor performance with widened potential windows − A microwave-assisted synthesis

Designing of high-performance supercapacitors with superior energy storage capabilities is crucial for addressing the growing demand for sustainable energy solutions. In this study, we investigate the synergistic effect of a sulfonated graphene oxide (SGO) /nickel-cobalt sulfide (NiCoS) nanocomposite on Ni-foam for supercapacitor applications. The SGO/NiCoS nanocomposite exhibits improved electrochemical performance, including increased specific capacitance, enhanced rate capability, and widened operating potential windows. The material exhibits a high energy density of 117.76 Wh/kg and a power density of 503.24 W/kg. The ASC also showed superior electrochemical stability, retaining 90 % of its coulombic efficiency after 10,000 cycles. The combination of NiCoS and SGO on Ni-foam significantly augments energy and power density, making it an attractive material for advanced supercapacitors. The microwave-assisted synthesis technique employed in this study enables rapid and uniform heating, reducing reaction times and improving selectivity. This work demonstrates the potential of SGO/ NiCoS nanocomposites on Ni-foam for supercapacitors, highlighting the benefits of synergistic material combinations and efficient synthesis methods.

381 (PB369): Adaptive Mechanisms and Synergistic Combinations to Overcome Sotorasib Resistance in KRASG12C-Driven NSCLC

381 (PB369): Adaptive Mechanisms and Synergistic Combinations to Overcome Sotorasib Resistance in KRASG12C-Driven NSCLC

Modulatory Role of Phytochemicals/Natural Products in Cancer Immunotherapy.

Immunotherapy is a newly emerging and effective approach to treating cancer. However, there are many challenges associated with using checkpoint inhibitors in this treatment strategy. The component of the tumor microenvironment plays a crucial role in antitumor immune response, regulating tumor immune surveillance and immunological evasion. Natural products/phytochemicals can modulate the tumor microenvironment and function as immunomodulatory agents. In clinical settings, there is a strong need to develop synergistic combination regimens using natural products that can effectively enhance the therapeutic benefits of immune checkpoint inhibitors relative to their effectiveness as single therapies. The review discusses immunotherapy, its side effects, and a summary of evidence suggesting the use of natural products to modulate immune checkpoint pathways.

High creep resistance in amorphous/crystalline dual-phase nanostructured CoCrFeNiMn high entropy alloys

Amorphous/crystalline dual-phase metallic materials received great attention owing to their synergistic combination of strength and ductility. However, the mechanisms governing creep deformation in these dual-phase materials are largely elusive. In the present letter, the creep deformation of amorphous/nanocrystalline CoCrFeNiMn high-entropy alloy (HEA) films is investigated through nanoindentation creep testing. It is suggested that dual-phase HEAs exhibit reduced creep strain compared to their monophase counterparts, and even surpass the performance of coarse-grained variants. This behavior arises from diffusion processes within the amorphous phase and the capacity for nucleation/annihilate of dislocations at amorphous/nanocrystalline interfaces. Furthermore, it is proposed that the presence of glass shell significantly influences the creep behavior of dual-phase HEAs.

Bimetallic Au-Ag Reduced Graphene Oxide Nanostructures for Enhanced Detection of Dengue Virus E Protein

The development of highly sensitive and specific diagnostic tools for early-stage detection of dengue virus (DENV) is critical for effective outbreak management, particularly in resource-limited settings. In this study, we report a novel electrochemical immunosensor based on bimetallic gold silver (Au-Ag) nanoparticles integrated with reduced graphene oxide (rGO) for the detection of dengue virus envelope (E) protein. The Au-Ag bimetallic nanostructures exhibit superior electron transfer kinetics and enhanced electrocatalytic activity, while rGO serves as an excellent platform due to its large surface area and high conductivity. This synergistic combination improves antigen-antibody interactions and significantly boosts sensor performance. The immunosensor demonstrated a broad linear detection range of 100 ag ml−1 to 10 ng ml−1, with a high correlation coefficient (R2 = 0.98519). It achieved an ultra-low limit of detection (LOD) of 4.959 ag ml−1 for DENV E protein, outperforming existing detection methods. These findings highlight the potential of the Au-Ag- rGO-based immunosensor as a promising tool for point-of-care diagnosis, enabling rapid and cost-effective disease management and control.

Integrated computational and experimental approaches to identify new papain-like protease inhibitors

SARS-CoV-2 papain-like protease (PLpro), a key viral protease, plays a crucial role in the viral replication and pathogenesis, making it an attractive target for the development of antiviral therapies. Thus to target PLpro, the chlorogenic acid was chosen based on its well-established characteristics as a natural compound with inhibitory properties against viral proteases. The research strategy involved a synergistic combination of in-silico and in-vitro techniques, enabled successful identification of a natural inhibitor for PLpro. In the docking analysis, it was observed that chlorogenic acid exhibited a more pronounced interaction energy with PLpro compared to GRL0617. Additionally, the molecular dynamics simulations demonstrated remarkable stability of the chlorogenic acid-PLpro complex, along with close proximity in conformational dynamics. The assessment of post-processing end-state free energies indicated comparable affinities for both molecules. Furthermore, the enzymatic inhibition assay performed for dose-response analysis provided validation for chlorogenic acid as a potential inhibitor of PLpro. This experimental assessment strengthens the evidence supporting the inhibitory activity of chlorogenic acid against PLpro. Overall, this comprehensive analysis serves as a valuable platform for the development of potential therapeutic candidates targeting PLpro, offering promising prospects for combating SARS-CoV-2.

Synergistic Structural Inhibition of MMP-9 by Natural Flavonoids: A Natural Combinatorial Therapy against Cancer

Introduction: Cancer is the uncontrolled proliferation of cells leading to metastasis due to genetic alterations resulting in oncogenes activation and tumor suppressor genes deactivation. It is the 2nd leading cause of death across the world. MMP-9 or gelatinase B, plays an effective role in ECM degradation, normal tissue turnover, and tissue remodelling. Methods: Overexpression of MMP-9 has been studied in almost all types of cancers proving the effective role of MMP-9 in accelerating malignant conditions. Thus, targeting MMP-9 to treat cancer seems to be a potential strategy to deal with adverse pathologies of cancer. Methods: Chemotherapy and radiotherapy are frequently utilized for the treatment of cancer but are associated with diverse side effects. Flavonoids are natural compounds frequently found in plants and have been analyzed for the structural inhibition potential against MMP-9 by several researchers to develop natural treatments against cancer, but none of the flavonoids have landed into clinical use. In the present study, in-depth in-silico analysis to investigate the synergistic effects of flavonoids for structural inhibition of MMP-9 was done. The ADMET and bioactive properties analysis revealed effective drug-like properties of the considered flavonoids. Principal component analysis of ADMET and bioactive properties revealed high similarity in the chemical nature of luteolin and quercetin. Molecular docking analysis of MMP-9 with the considered flavonoids individually revealed the highest effective binding energy of luteolin. Results: Combination docking analysis of MMP-9 with different combinations of flavonoids led to the identification of two combinations including Quercetin with Genistein and Luteolin and Genistein revealing high negative binding energies of -15.48kcal/mol and -15.31kcal/mol which was significantly greater than the binding energies identified for respective ligands in individual dockings. Conclusion: Thus, the present study put forward synergistic natural flavonoid combinations against cancer via the MMP-9 inhibition approach that can be further evaluated to develop high-efficacy treatments.