Antitumor Activity Research Articles

Innovating non-small cell lung cancer treatment with novel TM-GL/NPs nanoparticles for Glycitin delivery

Sojae semen praeparatum is a traditional Chinese medicine, and its active component, Glycitin, has shown potential in the treatment of non-small cell lung cancer (NSCLC). The purpose of this investigation is to examine the mechanism of action of the effective components of sojae semen praeparatum in the treatment of NSCLC, with a special emphasis on Glycitin, and to explore the integration of nanotechnology in delivering pharmaceutical agents. Key effective components were selected through network pharmacology analysis and functional analysis, and protein–protein interaction analysis and functional enrichment were performed using transcriptomics and metabolomics data to identify the key NSCLC-related target genes and regulatory mechanisms of action of the active components of sojae semen praeparatum. Glycitin-loaded NPs encapsulated in tumor-associated fibroblast membranes were developed to verify their characterization and safety, and their therapeutic effects in inhibiting the malignant phenotype of NSCLC cells through targeting the DNA topoisomerase II alpha (TOP2A) protein were validated. The results indicate that Glycitin exhibits significant anti-tumor activity by affecting the function of the TOP2A protein, thereby inhibiting tumor proliferation and metastasis. This research presents proof of the crucial function of Glycitin in managing NSCLC using sojae semen praeparatum, and sheds light on the possibilities of nanotechnology in drug delivery mechanisms, offering a novel avenue for NSCLC therapy research.

VSIG4+ tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1

V-set and immunoglobulin domain-containing 4 (VSIG4) positive tumor-associated macrophage (VSIG4+ TAM) is an immunosuppressive subpopulation newly identified in aggressive cancers. However, the mechanism how VSIG4+ TAMs mediate immune evasion in aggressive cancers have not been fully elucidated. In our study, we found targeting VSIG4+ TAMs by VSIG4 deficiency or blockade remarkably limited tumor growth and metastasis, especially those derived from anaplastic thyroid cancer (ATC) and pancreatic cancer, two extremely aggressive types. Moreover, the combination of VSIG4 blockade with a BRAF inhibitor synergistically enhanced anti-tumor activity in ATC-tumor bearing mice. VSIG4 deficiency recovered the antigen presentation (B2m, H2-k1, H2-d1) of TAMs and activated antigen-specific CD8+ T cells by promoting their in vivo proliferation and intratumoral infiltration. Notably, loss of VSIG4 in TAMs significantly reduced the production of lactate and histone H3 lysine 18 lactylation, resulting the decreased transcription of SPP1 mediated by STAT3, which collectively disrupted the cell-cell interactions between TAMs and neutrophils. Further combination of VSIG4 with SPP1 blockade synergistically boosted anti-tumor activity. Overall, our studies demonstrate the epigenetic regulation function of VSIG4 confers on TAMs an alternative pattern, beyond the checkpoint role of VSIG4, to shape the immunosuppressive tumor microenvironment and impair antigen-specific immunity against aggressive cancers.Graphical abstract

Recombinant CD80 fusion protein combined with discoidin domain receptor 1 inhibitor for cancer treatment

Immune checkpoint inhibitors (ICIs) have significantly advanced the field of cancer immunotherapy. However, clinical data has shown that many patients have a low response rate or even resistance to immune checkpoint inhibitor alone. The underlying reasons for its poor efficacy include the deficiency of immune infiltration and effective CD28/CD80 costimulatory signal in tumor. Discoidin domain receptor 1 (DDR1) has been reported to be negatively related to immune cell infiltration in tumors. Herein, we constructed a soluble fusion protein using CD80, the natural ligand of CD28, in combination with DDR1 inhibitor. Our results demonstrated that CD80-Fc effectively activated T cells and inhibited tumor growth in vivo, even in tumors with poor efficacy of ICIs. Importantly, CD80-Fc fusion protein had a milder affinity against the targets which suggested a potential higher safety than CD28 agonists. Further, in order to promote tumor immune infiltration, we attempted to combine CD80-Fc fusion protein with DDR1 inhibitor for treatment. Our results indicated that using CD80-Fc fusion protein along with DDR1 inhibitor significantly promoted T cell infiltration in tumor microenvironment and more strongly inhibited tumor growth. Therefore, the combination use of CD80 fusion protein and DDR1 inhibitor could become an effective tumor immunotherapy strategy, potentially benefiting a larger number of patients.Key points• We successfully constructed, expressed, and purified the recombinant CD80-Fc fusion protein• We demonstrated that CD80-Fc fusion protein has good safety and anti-tumor activity• We demonstrated that using CD80-Fc fusion protein along with DDR1 inhibitor can significantly promote immune infiltration of T cells in tumor microenvironment and more strongly inhibit tumor growth

Development of ASGR-Mediated Hepatocyte-Targeting Cytotoxic Drug Conjugates with CTSB-Cleavable Linkers Incorporating Succinimide and Succinic Acid Monoamide.

The ASGR-mediated endocytosis has been successfully applied to the hepatocyte-targeted delivery of therapeutic oligonucleotides via glycoconjugates. However, few studies have explored the conjugated small molecules due to the challenge of cleaving suitable linkers for the release of active small molecules, which is especially different from GalNAc-ONs cleaved by the deoxyribonuclease II in the lysosome. In this study, GalNAc-MMAE conjugates linked by CTSB-cleavable linkers were designed and synthesized. A comprehensive approach revealed that the conjugates were endocytosed by ASGR and subsequently hydrolyzed by CTSB, releasing MMAE. The optimized conjugate with a succinic acid monoamide as the fragment of the linker demonstrated favorable plasma stability, excellent biodistribution, and significant antitumor activities in vivo with weight gain at the effective dose in an orthotopic hepatocellular carcinoma mouse model. This research provides a strategy for developing anti-HCC therapeutic agents using GalNAc drug conjugates with CTSB-cleavable linkers to release active small molecules.

Cryptotanshinone Inhibits Obesity-Related Cervical Cancer by Down-Regulating CXCL8 Expression in Hela Cells.

Cervical cancer isone of the cancerscommonly found in the female reproductive systemand isassociated with obesity.However, the exact connection mechanisms remain unclear.Screening of key therapeutic targets and natural products with good anti-tumor activity has become a crucial strategy for cancer therapy.Cryptotanshinonehas anti-inflammatory and anti-cancer properties.Key therapeutic targets and related low-toxicity natural active ingredients were identified as crucial components in cancer treatment strategies.Therefore, network pharmacology and cellular biology techniques were used to screen and validatekey targets in obesity-related cervical cancer and to elucidate the mechanisms. The results indicated that C-X-C motif chemokine ligand 8 (CXCL8) might be modulated by cryptotanshinone.The knockdown of CXCL8significantly reduced Hela cell viability to 15.29 ± 4.59% compared with the control group (p<0.01), which consequently inhibited both cell proliferation and lipid droplet formation.Moreover, cryptotanshinone(20, 40, and 80 μM) significantly reduced CXCL8 expression and inhibited the NOD-like receptor signaling pathway in Hela cells compared with the control group (p<0.01). Therefore, this study manifested that cryptotanshinonepotentiallyplayed animportant role in obesity-related cervical cancer. This study providedthe important experimental basis for further exploring the pathogenesis and prevention of obesity-related cervical cancer.

Escherichia coli combination with PD-1 blockade synergistically enhances immunotherapy in glioblastoma multiforme by regulating the immune cells

BackgroundGlioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy. It is characterized by insufficient infiltration of anti-tumor T lymphocytes within the tumor microenvironment (TME), rendering it an “immune cold” disease. This immune deficiency results in poor responses to immune checkpoint blockade (ICB) therapies. Recent studies have demonstrated that bacteria can proliferate within tumors and activate immune responses. Therefore, in this study, we employed Escherichia coli (E. coli) in combination with anti-PD-1 antibodies to treat GBM, with the aim of exploring the immune-activating potential of E. coli in GBM and its synergistic effect on anti-PD-1 therapy.MethodsThe E. coli and anti-PD-1 antibody therapy were administered intravenously and intraperitoneally, respectively. Complete blood cell count, blood biochemical analysis, hematoxylin and eosin (H&E) staining, and agar plate culture were employed to evaluate the biosafety and tumor-targeting capability of E. coli. ELISA kits were used to detect innate immune cytokines. Flow cytometry and immunofluorescence staining were used to investigate T cells. Tumor volume of tumor-bearing mice was recorded to evaluate the combined treatment efficacy. H&E staining and immunofluorescence staining were used to observe the tumor inhibition markers.ResultsE.coli can specifically target into the tumor region, and activate the innate immune response in mice. Immunofluorescence staining and flow cytometry results demonstrated that the combination treatment group exhibited a significant upregulation of cytotoxic CD8+ T cells and a marked suppression of regulatory T cells compared to the control group. The expression of Ki67 was significantly downregulated, and TUNEL staining revealed an increased number of apoptotic cells in the combination treatment group. Furthermore, the tumor growth rate in the combination treatment group was significantly slower than that in the control group.ConclusionsE. coli exhibits potential anti-tumor activity and can activate the innate immune response and further regulate immune cells in the tumor tissues to synergize the effect of anti-PD-1 therapy on GBM, providing new insights to enhance the efficacy of GBM immunotherapy.

Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500.

The tumor microenvironment (TME) in solid tumors contains myeloid cells that modulate local immune activity. STING signaling activation in these myeloid cells enhances local type I interferon (IFN) production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. Here, we generated TAK-500, an immune cell directed antibody drug conjugate (iADC), to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to non-targeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 iADC surrogate enhanced innate and adaptive immune responses both in vitro and in murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the TME of >1,000 primary human tumors showed the CCR2 protein was predominantly expressed in intratumoral myeloid cells. Collectively, these data highlight the clinical potential of delivering a STING agonist to CCR2+ cells.

Anti-LAG-3 antibody LBL-007 plus anti-PD-1 antibody toripalimab in advanced nasopharyngeal carcinoma and other solid tumors: an open-label, multicenter, phase Ib/II trial

PurposeOpen-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors.MethodsPatients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy.ResultsBetween November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression.ConclusionLBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.

IFN-γ Approaches in Tumor Suppression, Its Challenges, and Future Directions: A Review of Recent Advances.

IFN-γ is recognized as an immunoregulatory cytokine due to its dual role in both accelerating and dampening immunological responses. Accordingly, in the context of tumor immunotherapy, the therapeutic outcome of IFN-γ is contingent upon factors such as dosage and the expression status of downstream signaling molecules. Furthermore, the coadministration of IFN-γ with various immunestimulatory agents, including anticheckpoint inhibitors, chemotherapeutic agents, and herbal-based medicines, may potentially overcome the IFN-γ-related challenges and enhance the response rate. We decipher the mechanisms of tumor cell eradication facilitated by IFN-γ, the last achievements in IFN-γ-mediated tumor immunotherapy across various cancers, and the strategies to address the failure of IFN-γ-based tumor immunotherapy. Unraveling the molecular mechanisms that lead to failure in IFN-γ-based antitumor actions could assist in pinpointing therapeutic agents that target the immune-modulatory features of IFN-γ, thereby increasing the antitumor response rate.

Phase I study of efineptakin alfa (NT-I7) for the treatment of Kaposi sarcoma

BackgroundCD4+ T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS...

Comparative Evaluation of the Antibacterial and Antitumor Activities of Marine Alkaloid 3,10-Dibromofascaplysin

Fascaplysins form a group of marine natural products with unique cationic five-ring coplanar backbone. Native fascaplysin exhibits a broad spectrum of bioactivities, among which the cytotoxic activity has been the most investigated. Several fascaplysin derivatives have more selective biological effects and are promising as lead compounds. Thus, the introduction of a substituent at C-9 of fascaplysin leads to a strong increase in its antimicrobial properties. Here, a comparative assessment of the antimicrobial activity of synthetic analogs of the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin, along with some of their isomers and analogs, was carried out against a panel of Gram-positive bacteria in vitro. For the first time, a significant increase in the antimicrobial activity of fascaplysin was observed when a substituent was introduced at C-3. The introduction of two bromine atoms at C-2 and C-9 enhances the antimicrobial properties by 4 to 16 times, depending on the tested strain. Evaluation of the antimicrobial potential in vivo showed that fascaplysin and 3,10-dibromofascaplysin had comparable efficacy in the mouse staphylococcal sepsis model. Additionally, 3,10-dibromofascaplysin demonstrated a strong and reliable antitumor effect in vivo on the Ehrlich carcinoma inoculated subcutaneously, with a value of tumor growth inhibition by 49.2% 20 days after treatment. However, further studies on alternative chemical modifications of fascaplysin are needed to improve its chemotherapeutic properties.

Proteolysis-Targeting Chimera-Doxorubicin Conjugate Nanoassemblies for Dual Treatment of EGFR-TKI Sensitive and Resistant Non-Small Cell Lung Cancer.

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. However, traditional PROTACs face inherent limitations and may also contribute to induce drug resistance. These challenges have driven the development of innovative strategies to overcome these obstacles. In current study, a PROTAC-DOX conjugates (PDCs) nanoassembly strategy was introduced to enhance tumor-targeting capability and overcome the drawbacks of conventional PROTACs. The designed PDC-S nanoparticles (PDC-S NPs) demonstrated potent anti-tumor activity against drug-resistant strains (IC50 = 4.7 µM) and improved in vivo efficacy (TGI = 76%) against drug-sensitive strains, while minimizing side effects. Additionally, PDC-S NPs have great potential in tumor immunotherapy. This study provides a novel and promising strategy for the development of PROTAC-Drug Conjugates (PDCs). STATEMENT OF SIGNIFICANCE: We developed a PROTAC-DOX conjugate (PDC) nanoassembly strategy to address the limitations of traditional PROTACs, such as poor solubility, low targeting specificity, and drug resistance. PDC-S NPs were constructed via self-assembly, which simplified preparation and minimized the toxicity typically associated with carrier-assisted delivery systems. The PDC-S NPs showed improved aqueous solubility and cellular uptake, resulting in efficient EGFR degradation in HCC827 cells. In vivo, PDC-S NPs accumulated at tumor sites via the EPR effect, resulting in enhanced anti-tumor potency with reduced side effects. Furthermore, PDC-S NPs induced immunogenic cell death (ICD) and suppressed PD-L1 and VEGF expression, showing great potential in tumor immunotherapy.

Purified Monascus Pigments: Biological Activities and Mechanisms of Action.

Monascus pigments having yellow, orange, and red colors are widely studied for their potential beneficial properties. Many different biological activities have been reported regarding Monascus pigments and their derivatives, but the usual method is to test complex extracts from the mycelium of the fungus or from a fungus-fermented substrate. However, this review is mainly concerned with the biological activities of purified Monascus pigments. Both yellow (ankaflavin, monascin) and red (rubropunctamine, monascorubramine) Monascus pigments are proven antioxidants if used in concentrations of 10 μg/mL or higher. Antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi has been observed with all Monascus pigments. However, the best antimicrobials are red Monascus pigments, and their amino acid derivatives (l-cysteine derivatives have MIC 4 μg/mL against Enterococcus faecalis). Yellow monaphilones and orange monaphilols seem to have the highest anti-inflammatory activity (IC50 1.7 μM of monaphilol D) and, together with red Monascus pigment derivatives, have mild antiobesity and antidiabetic activities. Further, monascin and ankaflavin in daily doses of 0.5 and 0.08 mg, respectively, lowered serum blood levels of low-density lipoprotein cholesterol complexes in rats on a high-fat diet. Orange Monascus pigments, rubropunctatin and monaphilols A and C, exhibit cytotoxic and antitumor activities (IC50 8-10 μM).

Cannabidiol attenuates lipid metabolism and induces CB1 receptor-mediated ER stress associated apoptosis in ovarian cancer cells

Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process. As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been confirmed to exhibit antitumor activity in preclinical studies. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells. In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a cannabinoid receptor type 1 (CB1R)-mediated manner. Fatty acid metabolic profiling and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced, dose-dependent, ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction. Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.

GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8+ T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer.

Recruitment of polymorphonuclear MDSCs (PMN-MDSCs) in the TME suppresses the antitumor activity of tumor-infiltrating CD8+ T cells (CD8+ TILs). Little is known about the role of antitumoral CD8+ TILs in actively initiating an immune-tolerant microenvironment, particularly in the recruitment of PMN-MDSCs. In this study, we found that immunotherapy-activated CD8+ TILs significantly increased PNM-MDSC infiltration in the TME, resulting in antitumor resistance. When CD8+ T cells are activated, lipocalin-2 (LCN2) expression is strongly upregulated, which significantly enhances PMN-MDSC chemotaxis. Mechanistically, immune activation increased fatty acid synthesis in CD8+ T cells, particularly oleic acid (OA), which induced lysosomal membrane permeabilization, releasing cathepsin B and subsequently activating NF-κB to promote LCN2 expression. Moreover, we showed that glucagon-like peptide 1 (GLP1) effectively inhibited OA synthesis in activated CD8+ T cells, reducing LCN2 production. We then developed a recombinant adenovirus encoding GLP1 (AdV-GLP1), which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8+ TILs. In various pancreatic cancer models, including subcutaneous, orthotopic, and humanized CDX/PDX models, AdV-GLP1 displayed excellent antitumor efficacy. Our work advances the understanding of how immunotherapy-activated CD8+ TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improve cancer immunotherapy.

Molecular Engineering of Cordycepin Derivatives for Enhanced Biological Activity and Stability.

To address the metabolic instability of cordycepin induced by adenosine deaminase (ADA) and to enhance its bioactivity, this study developed eleven novel cordycepin derivatives using molecular engineering techniques. By incorporating sterically hindered protective groups and modifying the glycosyl moiety, the research aimed to improve both stability and efficacy. Antibacterial tests revealed that five derivatives showed significantly greater activity against pathogenic strains compared to cordycepin, with better compatibility with probiotics. Compound 2c demonstrated moderate antitumor activity against K562 and MGC-803 cells, with IC50 values of 42.21 μM and 27.79 μM, respectively. Additionally, compound 4b demonstrated notable DPPH free radical scavenging ability. These compounds also showed improved stability in ADA solutions, providing valuable insights into the structure-activity relationships of cordycepin derivatives.

Phaseolus acutifolius Recombinant Lectin Exerts Differential Proapoptotic Activity on EGFR+ and EGFR− Colon Cancer Cells and Provokes T Cell-Assisted Antitumor Responses in Mice

Background: rTBL-1, a recombinant lectin from Phaseolus acutifolius, exhibit proapoptotic activity on colon cancer cells and inhibitory properties on colon tumorigenesis in vivo. Apoptosis has been associated with a phospho-EGFR/phospho-p38/phospho-p53 mechanistic axis. Immunogenicity data have been observed in treated animals, but its possible involvement in the antitumor response remained unexplored. Objective: We investigated whether the cytotoxic activity of rTBL-1 depends on EGFR and its capacity to produce antitumor responses on syngeneic colon cancer in mice, with and without T cells, in order to explore its possible involvement in the process. Results: rTBL-1 exhibited cytotoxic effects in a concentration-dependent manner in both EGFR+ (MC-38) and EGFR− (CT-26) colon cancer cells with LC50 values of 23.50 and 30.01 µg/mL, respectively (p = 0.063). Apoptotic effects were slower and longer-lasting in MC-38 than in CT-26 cells. Significant increases in caspase-3 proteolytic activation and PARP1 cleavage were detected in both cell types, despite PARP1 rheostasis in CT-26 cells. Intralesional treatment with rTBL-1 inhibited the growth of established tumors in immunocompetent BALB/c mice in 27.81% (p = 0.0008) with a benefit in survival (p = 0.022), but not in immunodeficient BALB/c nude mice. Conclusions: rTBL-1 induces apoptosis in colon cancer cells by EGFR independent mechanisms, although its presence could be related to deeper responses. Unresponsiveness in nude mice indicated that rTBL-1 antitumor effect is the synergistic result of apoptosis induction and T cell-mediated cytotoxicity in the tumor. Future studies will focus on the immunogenic effects triggered by the antitumor activity of rTBL-1 in colon cancer.

The Mode of Action and Clinical Outcomes of Sacituzumab Govitecan in Solid Tumors.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR+/HER2- breast cancer, and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti-Trop-2 monoclonal antibody (sacituzumab; hRS7) via a hydrolysable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ~8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2+ expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload-linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥ 3 treatment-emergent adverse events with SG, but they are manageable. Efficacy of SG has been demonstrated across a broad spectrum of solid tumors.

Unravelling anti-cancer properties of solanaceous extracts using GC–MS and HPLC

Cancer is a complex health issue that today’s medical science is dealing with, which has a mortality rate that is almost identical to that of cardiac disorders. Because of the adverse effects of the majority of the medications used in its therapy, managing it remains a major concern despite the availability of numerous remedies. This article attempts to contribute to the scientific developments in the Solanaceae family’s anti-cancer field. Thus, this study consisted of isolating β-amyrin, cedryl acetate, lupeol, and 2-pentadecanone, 6,10,14-trimethyl from Cestrum aurantiacum to determine the anti-tumor activity. The plant material was dried, pulverized, and small-scale extraction was done. Brine shrimps, cell lines (A549, Hela, HEPG), and Caenorhabditis elegans were used initially to examine three solanaceous plant extracts (Solanum villosum (SV), Cestrum aurantiacum (CA), and Brugmansia suaveolens (BS)). The best results were shown by ethanol extract of Cestrum aurantiacum that why large-scale extraction and GCMS of this extract were done. The antitumor potential can be explained by the presence of β-amyrin, cedryl acetate, lupeol, and 2-pentadecanone, 6,10,14-trimethyl.

The paradoxical role of SERPINB5 in gastrointestinal cancers: oncogene or tumor suppressor?

SERPINB5, also known as Maspin, is a non-inhibitory member of the serine protease inhibitor superfamily. SERPINB5 exerts diverse effects on a variety of human cancers, including cell proliferation, angiogenesis, apoptosis, tumor invasion, and metastasis. SERPINB5 has traditionally been regarded as a tumor suppressor gene, but emerging evidences supports its oncogenic properties. We conducted a comprehensive review of the existing literature on SERPINB5 in gastrointestinal cancers, synthesizing data on its expression patterns, subcellular localization, epigenetic modifications, and clinical significance. Depending on its subcellular localization and epigenetic modifications, SERPINB5 demonstrate either protumor or antitumor activity in different gastrointestinal cancers, such as colorectal cancer, gastric cancer, pancreatic cancer, gallbladder cancer and liver cancer. We elucidate its potential as a predictive and prognostic biomarker, with a focus on its implications for diagnosis, prognosis, and therapeutic intervention, emphasizing its utility in early lesion detection and treatment. SERPINB5 plays a complex and context-dependent role in gastrointestinal cancers, highlighting further research to dissect the true significance of SERPINB5 expression and the molecular mechanisms underlying its divergent clinical behaviors in cancer.