Antimetastatic Activity Research Articles

Antitumoral effectiveness and safety of intravenous versus subcutaneous administration of immunomodulatory peptide GK-1 in a murine breast cancer model.

GK-1 is a safe and effective molecule with high antimetastatic activity against murine breast and skin cancer. GK-1 treatment enhances cytotoxic response of CD8+ lymphocytes against the tumor and modifies the oxidative stress in the tumor. This study was designed to compare the antitumor efficacy of GK-1 by subcutaneous (SC) versus intravenous (IV) route of administration in the 4T1 mouse mammary carcinoma model and to extend its innocuity in heart and kidney, key tissues for observing damage induced by anticancer drugs and immunotherapy. BALB/c female mice were injected orthotopically with 1000 4T1 cells. When palpable primary tumors of about 1mm3 were detected, GK-1 (5mg/kg) was administered IV or SC weekly for 21days. Tumor growth and mouse weight were monitored weekly. The primary tumor weight and volume, the number of lung metastases, and programmed cell death protein 1 (PD-1) expression were recorded after 28days of starting treatment. Kidney, heart, spleen, serum, and blood samples from naïve mice were obtained to evaluate the safety of GK-1 administration by measuring the degree of damage to these tissues with specific cytotoxic markers. Subcutaneous or intravenous administration of GK-1 significantly increased the lifespan of mice and significantly reduced the primary tumor weight and volume and the number of lungs macrometastases. GK-1 reduced the expression of PD-1 in tumor-infiltrating lymphocytes in mice regardless of the route of immunization used, which is especially encouraging. No evidence of damage to kidney or heart tissues was detected in the tumor-free mice. This study supports that subcutaneous GK-1 administered, has an efficacy non-inferior to intravenous administration, well-tolerated with a similar safety profile and therefore offers a less invasive valid treatment alternative.

Quercetin triggers cell apoptosis-associated ROS-mediated cell death and induces S and G2/M-phase cell cycle arrest in KON oral cancer cells

BackgroundPlant flavonoids such as quercetin are useful for both the therapeutic and preventive care of a variety of illnesses. Nevertheless, their antitumor efficacy against KON oral cancer is still unknown. Therefore, the aim of this investigation was to examine quercetin’s anti-growth, anti-migrative, and anti-invasive characteristics. The cell cycle arrest property and mitochondrial function disruption of quercetin were also investigated. Additionally, the cellular mechanism responsible for inducing apoptosis and the anti-metastasis mechanism were identified.MethodsKON cells were treated with quercetin in order to test the anticancer activity of this compound. The MTT colorimetric assay was used to examine the cell viability of the treated cells in comparison to MRC-5 fibroblast cells. After being exposed to the detrimental effects of quercetin, the morphology of the KON cells was examined using DAPI and FDA double staining, as well as Hoechst 33,258 and AO double staining. Annexin V-FITC with a flow cytometer and DCFDA labeling were used to detect apoptosis induction and the ROS production associated with cell death. Quercetin’s ability to stop the cell cycle was evaluated via PI staining and the flow cytometer. The examination included anti-proliferative, anti-migration, and anti-invasion activities. Values for the transepithelial electrical resistance, or TEER, were measured. Ultimately, the mechanisms of action of the apoptotic markers and genes implicated in the metastatic process were clarified.ResultsQuercetin treatment reduced the vitality of KON cells and had minimal effect on MRC cells. Following quercetin treatment, the characterization of apoptosis and cell death in KON cells was observed. When quercetin was applied to KON cells, the generation of ROS increased. Furthermore, it was discovered that quercetin increased the percentage of dead cells and cell cycle arrests in the S and G2/M phases. Moreover, quercetin inhibited KON cells’ capacity for migration and invasion in addition to their effects on cell stability and structure. As a result of identifying the mechanism responsible for inducing apoptosis and preventing metastasis, quercetin was found to downregulate the expression of BCL-2/BCL-XL while increasing the expression of BAX. TIMP-1 expression was upregulated while MMP-2 and MMP-9 were downregulated. Quercetin’s anticancer properties and specific mechanisms of action in relation to KON cells were clarified.ConclusionQuercetin is greatly cytotoxic in oral cancer cells, triggering cells undergoing apoptosis and ROS-mediated cell death, possessing S and G2/M cell cycle arrest properties, and exhibiting anti-metastatic activities. Finally, this discovery opens up a wide range of possibilities for developing an anti-oral cancer drug and further investigating its effectiveness in vivo and in clinical trials as an alternative cancer treatment.

Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors.

Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (ACTB) and γ-actin (ACTG1) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.

Anticancer Activity of Plant Tocotrienols, Fucoxanthin, Fucoidan, and Polyphenols in Dietary Supplements.

Background: Plants and algae harbor diverse molecules with antioxidant activity and have been demonstrated to directly inhibit cancer cell growth and mitigate the oxidative damage associated with certain antitumor therapies. While antioxidant supplementation, either alone or in combination with chemotherapy, has shown promise in improving quality of life, further research is needed to explore the effects of antioxidant combinations on specific cancer cell lines. Methods: In this study, the in vitro cytotoxic and apoptotic properties of natural compounds derived from plants and algae, as well as certain dietary supplements, were investigated against various human cancer cell lines, including bone, leukemia, colorectal, breast, and prostate cancers. Results: Apple polyphenols, fucoxanthin, and plant-derived tocotrienols exhibited cytotoxic effects across all lines; however, tocotrienols demonstrated the most potent, time-dependent cytotoxic activity, with a half-inhibitory concentration (IC50) of 4.3 μg/mL in bone cancer cells. Analysis of dietary supplements 2.1, 4.0, and 10.0 revealed that supplement 10.0 exhibited specific cytotoxic activity against bone cancer line TIB-223 and colorectal cancer cell line Caco2, with IC50 values of 126 μg/mL and 158 μg/mL, respectively. Both tocotrienols and supplement 10.0 induced morphological changes in TIB-223 cells, inhibited cell migration (anti-metastatic activity), and promoted apoptosis, as evidenced by caspase 3/7 activation in both bone and colorectal cancer cells. Conclusions: These findings provide valuable insights for the development of targeted dietary supplements to enhance the anticancer effect of conventional chemotherapy in specific cancer types.

Garcinol, a natural benzophenone overcomes radio and chemoresistance by targeting PI3K-PKB/AKT pathway in rhabdomyosarcoma cells

AKT signaling pathway is a critical intracellular signaling pathway involved in regulating various cellular processes, including cell proliferation, cell survival, cell migration and metabolism. Cancer cells have a propensity to alter the expression of pro- and anti-angiogenic signals to activate the angiogenic switch. Aberrant overexpression of AKT pathway is associated with various types of cancers and enables the migration and invasion of tumor cells to neighboring tissues. Garcinol, a natural benzophenone, displays potent anticancer potential against various cancer cells, but its mechanism of action in inducing apoptosis remains unclear. The present study aimed to unveil the mechanism of action of garcinol in inducing apoptosis in rhabdomyosarcoma cells. Garcinol inhibited cell proliferation, reduced the viability of cancer cells, diminished colony formation, and mitigated the migratory capabilities of Rh cells. In vitro analysis of garcinol unveiled potent anticancer and anti-metastatic activity, with an IC50 ranging from 5.32 to 16.28 against Rh cell lines, as demonstrated by MTT assay. Garcinol actuates apoptosis by triggering mitotic arrest (G2/M phase arrest) in Rh cell lines and alters the expression of pro-apoptotic and anti-apoptotic proteins to trigger efficient apoptosis in cancer cells.

A randomized controlled study of neoadjuvant metformin with chemotherapy in nondiabetic breast cancer women: The METNEO study.

Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor-related apoptosis-inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy. We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC-T chemotherapy (4cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2, followed by 12 cycles of weekly paclitaxel 80 mg/m2) or AC-T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells. The overall clinical response (odds ratio: 22.67 [2.77-185.18], P= .004), breast-conserving surgery (odds ratio: 3.67 [1.303-10.321], P= .014) and pathological complete response (β =2.49 ±1.13 [0.274-4.712], P= .028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ±0.25 vs. 4.87 ±0.53, P= .0003) and DR5 (0.21 ±0.25 vs. 4.29 ±0.95, P= .0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs. 100.00%, P< .0001) and nuclear sites (4.35 vs. 95.00%, P< .0001). Metformin improves clinical and pathological responses to neoadjuvant AC-T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465).

The Anti-Metastatic Potential of Aronia Leaf Extracts on Colon Cancer Cells.

Numerous studies have demonstrated the health benefits of polyphenols found in aronia fruits; however, little is known about how aronia leaf polyphenols impact colorectal cancer (CRC). This study aimed to evaluate the in vitro anti-metastatic and anti-invasive activity of crude aronia leaf extract (ACE) and purified phenolic-rich aronia leaf extract (APE) against two CRC cell lines (SW-480 and HT-29). Migration and invasion potential of ACE and APE were evaluated. Moreover, ELISA and gelatin zymography were performed to detect translational and activity changes in CRC cells after aronia extracts treatment. We found that a 100 µg/mL concentration of ACE and APE almost entirely downregulated the migration and invasion of SW-480 cells, showing greater effectiveness than HT-29 cells. The observed inhibition was concentration-dependent and statistically significant. Additionally, extracts reduced the product of MMP-2 and MMP-9 gene expression at the protein level and simultaneously inhibited the activity of both MMPs. An APE at 300 µg/mL for SW-480 and 600 µg/mL for HT-29 resulted in a notable reduction in MMP-2 protein synthesis by 72% and 50%, respectively. In contrast, MMP-9 protein synthesis decreased by 48% and 59% in HT-29 cells treated with 300 µg/mL and 600 µg/mL of ACE, respectively. The levels of gelatinase activity were similar for both CRC lines, and the APE tested at a concentration of 300 µg/mL reached almost the IC50 value after 48 h of incubation. Based on the presented results, we provided an experimental foundation for future in vitro and in vivo studies on the potential effects and activities of aronia leaves.

In vitro and in silico studies of a Zn(II) complex as a potential therapeutic agent for breast cancer.

Breast cancer (BC) is one of the most life-threatening diseases of women's health worldwide. This work was conducted to assess the anti-BC potency of a new Zn(II)-based complex. The Zn(II) complex coordinated to dimethoxy-substituted bipyridine was synthesized and its molecular structure was elucidated as [Zn(2Meobpy)3](clo4)2 (2Meobpy-Zn) by single-crystal X-ray diffraction, 2Meobpy represents 4,4'-dimethoxy-2,2'-bipyridine. The cytotoxicity results indicated that 2Meobpy-Zn, unlike cisplatin, acts potently and selectively on the human breast cancer cells (MCF-7) compared to normal murine embryo cells (NIH/3T3) by IC50 value of 4.6 ± 0.5µm and selectivity index (SI) of 2.0 over 48h. 2Meobpy-Zn and cisplatin showed anti-metastatic activity as evidenced by inhibition of the colony formation and cell migration. The flow cytometric assessment of MCF-7 cells supported that 2Meobpy-Zn and cisplatin exert their cytotoxic effect through the apoptotic pathway. Moreover, 2Meobpy-Zn could induce overproduction of intracellular reactive oxygen species (ROS) in MCF-7 cells. The apoptotic mechanism in 2Meobpy-Zn-treated MCF-7 cells is probably related to the regulation of apoptosis-relevant genes expression, including BAX and BCL2. Moreover, 2Meobpy-Zn is able to cleave pUC19 plasmid DNA through the hydrolytic reaction pathway. Finally, 2Meobpy-Zn's affinity towards antiapoptosis-related proteins, as a potential apoptosis inducer, as well as breast cancer-relevant proteins, as a potential anti-BC agent, was evaluated by in silico molecular docking studies. Altogether, the results of this work strongly evidenced that 2Meobpy-Zn can be the subject of experimental validation and clinical trials to introduce this complex as a promising BC therapeutic agent.

DNA binding, and apoptosis-inducing activities of a β-ionone-derived ester in human myeloid leukemia cells: multispectral and molecular dynamic simulation analyses

β-Ionone is the end-ring counterpart of β-carotenoids, which are widely found in fruits and vegetables. Recent studies have illustrated the antimetastatic, anti-proliferative, and apoptosis-inducing activities of β-ionone both in vitro and in vivo. We aimed to explore the anti-cancer potency of β-Ionone-derived ester, (E)-4-(2,6,6-trimethylcyclohex-1-enyl) but-3-en-2-ylpyrazine-2-carboxylate (4-TM.P). The cytotoxic effects of the compound on K562 cells were evaluated by MTT assay. The mechanisms of apoptosis induction were investigated by acridine orange/ethidium bromide (AO/EtBr) double staining, cell cycle analysis, and Annexin V/PI staining. Furthermore, the 4-TM.P-DNA interactions have been thoroughly elucidated by various methods, such as ultraviolet–visible spectroscopy, fluorescence assays, viscosity measurements, molecular docking, and dynamic simulation. The MTT cytotoxicity assay revealed that the growth of K562 cells was inhibited by treatment with β-ionone-derived ester, with an IC50 of 25 ± 5.0 µM at 72 h. Morphological studies revealed the occurrence of apoptosis in treated cells, and G0/G1 cell cycle arrest was observed after treatment of the cells with the IC50 value of the compound. Analyses of multi-spectroscopy and viscosity assays revealed that 4-TM.P binds to DNA in the minor groove mode, which was supported by molecular docking studies. The dynamic stability of the complex was also confirmed using molecular dynamic simulation analyses.

Leveraging long-acting IL-15 agonists for intratumoral delivery and enhanced antimetastatic activity.

IL-15 agonists hold promise as immunotherapeutics due to their ability to induce the proliferation and expansion of cytotoxic immune cells including natural killer (NK) and CD8+ T cells. However, they generally have short half-lives that necessitate frequent administration to achieve efficacy. To address this limitation, we have developed a half-life extension technology using hydrogel microspheres (MS). Here, the therapeutic is tethered to MSs by a releasable linker with pre-programed cleavage rates. We previously showed the MS conjugate of single-chain IL-15, MS~IL-15, effectively increased the half-life of IL-15 to approximately 1 week and enhanced the pharmacodynamics. We sought to determine whether the same would be true with a MS conjugate of the IL-15 agonist, receptor-linker IL-15 (RLI). We prepared a long acting MS conjugate of RLI, MS~RLI. The pharmacokinetics and pharmacodynamics of MS~RLI were measured in C57BL/6J mice and compared to MS~IL-15. The antitumor efficacy of MS~RLI was measured when delivered subcutaneously or intratumorally in the CT26 tumor model and intratumorally in the orthotopic EO771 tumor model. MS~RLI exhibited a half-life of 30 h, longer than most IL-15 agonists but shorter than MS~IL-15. The shorter than expected half-life of MS~RLI was shown to be due to target-mediated-disposition caused by an IL-15 induced cytokine sink. MS~RLI resulted in very potent stimulation of NK and CD44hiCD8+ T cells, but also caused significant injection-site toxicity that may preclude subcutaneous administration. We thus pivoted our efforts toward studying the MS~RLI for long-acting intra-tumoral therapy, where some degree of necrosis might be beneficial. When delivered intra- tumorally, both MS~IL-15 and MS~RLI had modest anti-tumor efficacy, but high anti- metastatic activity. Intra-tumoral MS~RLI and MS~RLI combined with systemic treatment with other agents could provide beneficial antitumor and anti-metastatic effects without the toxic effects of systemic IL-15 agonists. Our findings demonstrate that intra-tumorally administered long-acting IL-15 agonists counter two criticisms of loco-regional therapy: the necessity for frequent injections and the challenge of managing metastases.

In Vitro Antitumor and Antimetastatic Activity of a New Lapachol Derivative against Metastatic Breast Carcinoma.

Breast cancer represents the most prevalent type of tumor throughout the world. Considering the side effects caused by the available treatments, the resistance acquired by cells to cytotoxic agents, and metastasis, it is necessary to search for new sources of antitumor and antimetastatic therapies. Given the numerous antitumor studies involving the synthesis of substances derived from the naphthoquinone lapachol, we investigated the antineoplastic potential of a new synthetic substance (APO-3) derived from lapachol, alone and in combination with the chemotherapeutic agent paclitaxel (PTX), against 4T1 cells, a murine breast cancer cell line. In MTT assay APO-3 and the APO-3/PTX combination were selectively cytotoxic to 4T1 cells, with APO-3/PTX being approximately 6.5 and 15 times more selective than PTX and APO-3, respectively. After zymography, APO-3/PTX was more effective in decreasing matrix metalloproteinase-9 (MMP-9) activity compared with APO-3 alone. In the clonogenic assay, APO-3/PTX reduced the number of colonies more effectively than APO-3 or PTX alone. APO-3/PTX also inhibited cell migration, as did PTX and APO-3 alone. The combination increased the expression of proteins involved in the intrinsic apoptotic pathway and induced cellular morphological changes characteristic of this type of cell death, acting similarly to PTX alone. APO-3 increased Receptor-interacting serine/threonine-protein kinase 1 (RIP1) and caused morphological changes characteristic of apoptosis and necroptosis in 4T1 cells. Taken together, APO-3 presented antitumor action against 4T1 cells, but the APO-3/PTX combination was more effective than either substance alone.

Timosaponin AIII Disrupts Cell–Extracellular Matrix Interactions through the Inhibition of Endocytic Pathways

Timosaponin AIII (TAIII), a steroidal saponin isolated from the root of Anemarrhena asphodeloides Bunge, exhibits various pharmacological activities, including anti-cancer properties. TAIII inhibits the migration and invasion of various cancer cell types. However, the mechanism underlying how TAIII regulates the motility of cancer cells remains incompletely understood. In this study, we demonstrate that TAIII disrupted cell-extracellular matrix (ECM) interactions by inhibiting internalization of cell surface proteins, such as integrins. We found that TAIII inhibited cell adhesion on various ECMs. Structure-activity relationship analysis demonstrated that TAIII exhibited unique activity among the saponins from Anemarrhena asphodeloides Bunge and that the number and position of saccharide moieties were important for TAIII to exert its activity. Time lapse imaging revealed that TAIII also suppressed cell spreading on the ECM, membrane ruffling, and lamellipodia formation. Furthermore, we examined integrin β1 behaviors in response to TAIII treatment and found that TAIII blocked its internalization. These findings contribute to delineating the potential molecular mechanisms by which TAIII exerts anti-metastatic activity.

Interleukin-12 treatment reduces tumor growth and modulates the expression of CASKA and MIR-203 in athymic mice bearing tumors induced by the HGC-27 gastric cancer cell line

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system and due to its poor prognosis, there is an increase in the demand for more effective anticancer therapies. Interleukins are potential anticancer agents which can modulate expression of cancer related genes and have therapeutic effects. Interleukin 12 (IL-12) exhibits potent anti-tumor, anti-angiogenic and anti-metastatic activities and represents the ideal candidate for tumor immunotherapy, due to its ability to activate both innate and adaptive immunities. The aim of this study was to evaluate the effect of IL-12 administration on GC tumor growth induced in the cancer xenograft nude mouse model. Tumor development was analyzed weekly and after 8 weeks, the animals were sacrificed for cytokine analysis (IL-4, TNF-alfa, IL-2, INF-gamma, IL-12, IL-10, TGF-beta) by ELISA. The tumor cells in the implanted areas of the animals that developed solid growth of the tumor (anatomopathological analysis was performed). We have also evaluated CASK and miR203 expression, two related cell invasion factors, in the induced tumors after administration of 6 n/kg IL-12. The development of tumor masses was observed in all groups of animals inoculated with HGC-27 neoplastic cells. In animals treated with 6 n/kg IL-12, there was no tumor development confirmed by anatomopathological analysis. Changes in the levels of pro and anti-inflammatory cytokines were also observed. Our results indicated that miR203 expression was elevated while CASK was downregulated. These results suggest that IL-12 treatment repress the tumor growth by induction of miR203 expression which in turn repress CASK expression.

Phytochemical screening, characterization, and in vitro anti-metastatic effects of the methanolic leaf extract of Momordica cardiospermoides in MDA-MB 321 cells

Introduction: Momordica cardiospermoides represents an inexhaustible source of natural products. We examined the acetone and methanolic extracts of M. cardiospermoides leaves’ phytochemical composition, antioxidant activities, and anti-metastatic properties in MDA-MB-231 cells. Methods: The aluminium chloride and Folin-Ciocalteu methods were employed to determine the extracts’ phytochemical contents. Assessment of antioxidant activities employed the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The extracts were further characterized with ultra-high-performance liquid chromatography (UHPLC). The cell count and viability kit were utilized to assess viability in HEK-293 and MDA-MB-231 cells. The occurrence of cell death was determined by the annexin V and dead cell assay. The methanolic extract was assessed against cell adhesion and migration using the cell-extracellular matrix and wound healing assays. The effects of the methanolic extract on tissue inhibitors, including metalloproteinase-1 (TIMP-1), matrix metalloproteinases-2 (MMP-2), and -9 (MMP-9) were determined by the human angiogenesis antibody array kit and Western blot analysis. Results: The acetone extract had higher antioxidant activity and total contents than the methanolic extract. UHPLC revealed abundant luteolin, luteoloside, quercetin, stearidonic acid, and salicylamide in the acetone extract, and luteolin, astragalin, and trigonelline in the methanolic extract. The methanolic extract was selectively cytotoxic towards MDA-MB-231 cells while the acetone extract was significantly cytotoxic in both cell lines. Apoptosis was induced by the methanolic extract and the acetone extract induced significant necrosis. The methanolic extract suppressed migration by significantly inhibiting wound closure and inhibited cell adhesion. MMP-2 and MMP-9 were significantly downregulated and TIMP-1 was upregulated. Conclusion: The methanolic extract M. cardiospermoides possesses anti-metastatic activity.

Unveiling the antimetastatic activity of monoterpene indole alkaloids targeting MMP9 in cancer cells, with a focus on pharmacokinetic and cellular insights

Distant metastasis, together with acquired resistance, limits the therapeutic impact of chemotherapy and molecularly targeted therapies. The properties of the tumor microenvironment determine how sensitive or resistant various cancers are to specific pharmacological treatments. Matrix metalloproteinase 9 (MMP9) is widely known for its ability to break down the extracellular matrix and it also modulates the motility of cancer cells. Here, our goal was to identify compounds that target MMP9 and evaluate their capacity to inhibit the motility of cancer cells. The anti-metastatic effect of monoterpene indole alkaloids (MIAs) on cell viability and motility was evaluated by MTT assay, migration assay, invasion assay, qRT-PCR, pathway-focusedexpression analysis, Western blotting, reporter assay, molecular docking simulation, and target prediction. MIA compounds target MMP9. MIAs inhibited the expression of p-EGFR, p-Akt, p-JNK and cyclin D1. Additionally, MIAs had predicted favorable pharmacokinetic profile and drug-like properties. Furthermore, among the MIA compounds lyaloside and 5(S)-5 carbomethoxy strictosidine had low cytotoxicity and regulated cancer-related signaling, including cell migration, cell invasion, epithelial–mesenchymal transition and immune evasion. Our findings demonstrated that the MIAs used in this study have potential anti-metastasis properties that occur via MMP9-mediated regulation of cancer signaling and have the potential to be used therapeutically at safe doses.

In vivo anti-tumor and anti-metastatic activity of renieramycin M and doxorubicin combination treatments on 4T1 breast cancer murine model

Breast cancer continues to be a serious global health concern, necessitating novel treatment approaches. This study explores the potential of combination therapies, investigating the combinatorial effects of doxorubicin (Dox) and renieramycin M (RM) in vivo, previously shown to have synergistic effects in vitro. Single drug administrations and combination treatments were tested on in vivo breast cancer murine models using 4T1-injected BALB/c mice. Tumor volume, animal mortality, and clinical toxicity were monitored, and in silico toxicity assessment was performed. Histopathological analyses using hematoxylin and eosin (H&amp;E) staining, and immunohistochemistry utilizing the p63 breast cancer marker were used for validation. The combination treatment of Dox and RM (5 mg/kg + 1 mg/kg) displayed a 46.53% reduction in tumor volume and an 83.63% decrease in observed metastatic infiltration in the liver. Furthermore, the combination treatment of Dox and RM significantly delayed and reduced the clinical signs of toxicity, as revealed by the decline in observed mortality as opposed to animal deaths in single drug treatments. Our study highlights the potential synergism between Dox and RM as combination therapy for breast cancer treatment. These findings provide possible strategies to improved therapies, offering a more effective and less toxic approach to mitigating breast cancer.

Mechanistic Insight into Anticancer Prowess of Piper Species and their Bioactive Compounds: A Review

Southern Asia boasts a diverse array of Piper species, renowned for their antimicrobial, antioxidant, and anti-inflammatory properties. These plants, also native to the American tropics, have played a significant role in traditional medicine and culinary practices. Notably, Piper longum L., P. nigrum L., and P. betle L. are recognized for their bioactive compounds, particularly alkaloids, which contribute to their beneficial properties. In recent decades, there has been increased focus on studying these plants for their potential anticancer effects, encompassing both direct cytotoxic effects and indirect modulation of the tumor microenvironment. Major scientific literature databases were consulted using appropriate keywords to present a comprehensive and proportionate analysis of the anticancer potential of the three species, including valuable insights into their therapeutic perspectives, molecular mechanisms, and broader applications in cancer treatment. Numerous pharmacological trials on the bioactive components and extracts have underscored their clinical significance, revealing multifaceted actions such as antiproliferative effects, antiangiogenic properties, immunomodulation, antimetastatic activity, induction of apoptosis, and modulation of various signaling pathways in both malignant and non-malignant disorders. Among the explored compounds, piperine and piperlongumine, prominent alkaloids within the Piper genus, have demonstrated notable efficacy in restricting the growth of cancer cells and tumors. This article emphasizes the biomedical and pharmacological findings related to the anticancer properties of the three Piper species, with a focus on their mechanism of action. These insights could open avenues for future clinical scenarios and therapeutic utilization of bioactive substances and extracts derived from these species.

Peptide Drones Facilitating the Transdermal Delivery of Antitumor Proteins for Melanoma Treatment

AbstractTopical treatment offers a viable alternative for melanoma patients incompatible with surgical interventions. Herein, the study develops a skin‐penetrating peptide (SPP)‐based peptide drone (PD) for the transdermal delivery of antitumor proteins. To achieve cost‐effective therapeutics, Concanavalin A (ConA), which can be prepared through an extraction method, is loaded onto PDs. Compared with free proteins, ConA‐PD complexes (CPCs) demonstrate significantly greater skin permeation. Moreover, the CPCs exhibit potent anticancer activity both in vitro and in vivo, which substantially surpass the efficacy of the Aldara (imiquimod) cream. The CPC‐treated mouse skin remains clear, whereas Aldara cream induces side effects, including psoriasis‐like skin inflammation. The antimetastatic activity of the PD is identified as another advantage of CPC. The use of ConA as an anticancer agent has been significantly limited due to its high hepatotoxicity; however, the transdermal delivery strategy minimizes its hepatic absorption and, in turn, results in negligible hepatotoxicity. These results demonstrate the potential of the CPC as a novel therapeutic agent or an adjunct to other modalities for melanoma treatment, overcoming the limitations of existing materials while exhibiting superior efficacy.

Enhanced anti-tumor and anti-metastatic activity of quercetin using pH-sensitive Alginate@ZIF-8 nanocomposites:in vitroandin vivostudy.

Quercetin (Qc) possesses anti-cancer properties, such as cell signaling, growth suppression, pro-apoptotic, anti-proliferative, and antioxidant effects. In this study, we developed an alginate-modified ZIF-8 (Alg@ZIF-8) to enhance the anti-tumor efficacy of Qc. The developed alginate-modified quercetin-loaded ZIF-8 (Alg@Qc@ZIF-8) was characterized using scanning electron microscope (SEM), dynamic light scattering (DLS), fourier transform infrared spectroscopy Thermogravimetric analysis, Brunauer-Emmett-Teller, and x-ray diffraction. The drug release pattern was evaluated at pH 5.4 and 7.4. The cytotoxicity of nanoparticles was assessed on the 4T1 cell line. Finally, the anti-tumor activity of Alg@Qc@ZIF-8 was evaluated in 4T1 tumor-bearing mice. SEM showed that the nanoparticles were spherical with a diameter of mainly below 50 nm. The DLS showed that the developed nanoparticles' hydrodynamic diameter, zeta potential, and polydispersity index were 154.9 ± 7.25 nm, -23.8 ± 5.33 mV, and 0.381 ± 0.09, respectively. The drug loading capacity was 10.40 ± 0.02%. Alg@Qc@ZIF-8 exhibited pH sensitivity, releasing more Qc at pH 5.4 (about 3.62 times) than at pH 7.4 after 24 h. Furthermore, the IC50value of Alg@Qc@ZIF-8 on the 4T1 cell line was 2.16 times lower than net Qc. Importantly, in tumor-bearing mice, Alg@Qc@ZIF-8 demonstrated enhanced inhibitory effects on tumor growth and lung metastasis compared to net Qc. Considering thein vitroandin vivooutcomes, Alg@Qc@ZIF-8 might hold great potential for effective breast cancer management.

Combined Chemo- and Photothermal Therapies of Non-Small Cell Lung Cancer Using Polydopamine/Au Hollow Nanospheres Loaded with Doxorubicin.

The chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity, posing challenges in its application for non-small cell lung cancer (NSCLC). This study aims to explore the efficacy of polydopamine/Au nanoparticles loaded with DOX for chemotherapy and photothermal therapy in NSCLC to achieve enhanced efficacy and reduced toxicity. Hollow polydopamine (HPDA)/Au@DOX was synthesized via polydopamine chemical binding sacrificial template method. Morphology was characterized using transmission electron microscopy, particle size and potential were determined using dynamic light scattering, and photothermal conversion efficiency was assessed using near-infrared (NIR) thermal imaging. Drug loading rate and in vitro drug release were investigated. In vitro, anti-tumor experiments were conducted using CCK-8 assay, flow cytometry, and live/dead cell staining to evaluate the cytotoxicity of HPDA/Au@DOX on A549 cells. Uptake of HPDA/Au@DOX by A549 cells was detected using the intrinsic fluorescence of DOX. The in vivo anti-metastasis and anti-tumor effects of HPDA/Au@DOX were explored in mouse lung metastasis and subcutaneous tumor models, respectively. HPDA/Au@DOX with a particle size of (164.26±3.25) nm, a drug loading rate of 36.31%, and an encapsulation efficiency of 90.78% was successfully prepared. Under 808 nm laser irradiation, HPDA/Au@DOX accelerated DOX release and enhanced uptake by A549 cells. In vitro photothermal performance assessment showed excellent photothermal conversion capability and stability of HPDA/Au@DOX under NIR laser irradiation. Both in vitro and in vivo experiments demonstrated that the photothermal-chemotherapy combination group (HPDA/Au@DOX+NIR) exhibited stronger anti-metastatic and anti-tumor activities compared to the monotherapy group (DOX). HPDA/Au@DOX nanosystem demonstrated excellent photothermal effect, inhibiting the growth and metastasis of A549 cells. This nanosystem achieves the combined effect of chemotherapy and photothermal, making it promising for NSCLC treatment.