Antineoplastic Compounds Research Articles

MDB-93. A TRANSCRIPTOME-BASED APPROACH TO DRUG REPURPOSING FOR AGGRESSIVE GROUP 3 MEDULLOBLASTOMAS

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in children, representing 20% of pediatric brain tumors. International consensus has identified molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4). Current treatments, guided by histologic tumor grade and stage, do not fully harness these subgroups, resulting in varying prognoses. G3MB particularly faces challenges with rapid recurrence and aggressive disease, necessitating focused intervention. METHODS We conducted differential expression analysis on MB patient datasets (GSE148389, GSE164677) to generate a G3MB gene expression signature. This gene expression signature was analyzed against the LINCS database, yielding candidate antineoplastic compounds. Candidates were filtered for blood-brain barrier permeability and FDA approval. Functional assays evaluated drug effects on cytotoxicity, clonogenicity, wound healing, cell cycle, and apoptosis in G3MB cell lines (HDMB03 and D425). RNA sequencing of treated cells identified differentially regulated pathways to infer mechanism, followed by in vitro validation. Mitochondrial function and membrane potential were measured by Seahorse and TMRM assays, respectively. RESULTS Eighty-one candidates passed filtering. The leading drug class identified was antidepressants. Based on MTT assays, the top four candidates were nortriptyline, simvastatin, fluoxetine, and sertraline. Nortriptyline (NT) emerged as the lead compound, with IC50 values of ~7uM (HDMB03) and ~11uM (D425). Amongst the four drugs, NT induced consistent anti-neoplastic effects on wound healing, colony formation, medullosphere generation, and apoptosis. Mechanistically, NT induced mitochondrial stress, escalated mitochondrial superoxide, and decreased mitochondrial membrane potential. CHRM3, a receptor antagonized by NT and upregulated in G3MB samples was downregulated by NT treatment. Western blotting confirmed the inhibition of CHRM3 downstream effectors. CONCLUSIONS Our pipeline identified cytotoxic compounds against G3MB, including NT, which we hypothesize induces mitochondrial stress via CHRM3 modulation. This approach offers repurposable FDA-approved candidates for high-risk G3MB, potentially reducing current treatment toxicity and improving outcomes.

Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice.

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

Abstract 3578: A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs

Abstract Neuroendocrine neoplasms (NENs) are rare cancers that arise from neuroendocrine cells. NENs are classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Small bowel NETs (SBNETs) and pancreatic NETs (PNETs) are generally slow growing but they commonly metastasize to the liver and can become aggressive cancers. NECs are rapidly growing, and patients have poor prognosis. Little is known about the drug sensitivity profile of SBNETs, PNETs and NECs due to a paucity of cellular and animal models of these malignancies. We have successfully cultured NEN cells from clinical samples as patient-derived spheroids (PDS) and showed that they express appropriate tumor markers. We systematically screened 20 NEN (12 SBNET, 5 PNET, and 3 NEC) spheroid cultures against a library of 175 compounds (147 FDA-approved anti-cancer drugs, 8 lab selected compounds, and 20 structurally diverse molecules) and compared their drug sensitivity profiles to identify the most effective drug classes and to better understand the biology of each NEN subtype. Top drug hits were validated for their anti-tumor properties in NEN PDS and patient-derived xenograft (PDX) mouse models. Our NEN PDS cultures identified common and unique drug sensitivity profiles for each type of NEN. SBNET spheroids were more resistant to many classes of anti-cancer drugs, which was due to overexpression of cytochrome P450 genes. Consistent with clinical findings, PNET spheroids showed increased sensitivity to tyrosine kinase and mTOR/PI3K inhibitors compared to SBNET & NEC spheroids. NEC spheroids showed the broadest sensitivity to many anti-neoplastic compounds. The top candidate drug identified from our screen was romidepsin, a histone deacetylase inhibitor. Romidepsin displayed anti-tumor properties in vitro and in vivo for all 3 NEN models and was highly synergistic with rapamycin, an mTOR inhibitor similar to the SBNET approved drug everolimus. Excitingly, low-dose romidepsin effectively inhibited tumor growth when combined with low-dose rapamycin in an SBNET PDX mouse model. These NEN PDS drug screens enabled direct drug testing in primary tumor cultures to identify promising drugs that could be used alone or in combination with currently approved-NEN therapies. Histone deacetylase inhibitors, such as romidepsin, may be effective against SBNETs. NEN PDS models also serve as a valuable resource for understanding the unique biology and mechanisms of drug resistance for specific NEN subtypes. Citation Format: Catherine G. Tran, Luis C. Borbon, Dane H. Tow, Jonathan Shilyansky, Guiying Li, James Egan, Scott K. Sherman, Ellen Abusada, Jing Tang, Ramaswamy govindan, Ryan C. Fields, Terry A. Braun, Carlos HF Chan, Chandrikha Chandrasekharan, Douglas Spitz, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po Hien Ear. A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3578.

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties.

Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.

Lysicamine Reduces Protein Kinase B (AKT) Activation and Promotes Necrosis in Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer (TC), accounting for 50% of total TC-related deaths. Although therapeutic approaches against TC have improved in recent years, the survival rate remains low, and severe adverse effects are commonly reported. However, unexplored alternatives based on natural compounds, such as lysicamine, an alkaloid found in plants with established cytotoxicity against breast and liver cancers, offer promise. Therefore, this study aimed to explore the antineoplastic effects of lysicamine in papillary TC (BCPAP) and ATC (HTH83 and KTC-2) cells. Lysicamine treatment reduced cell viability, motility, colony formation, and AKT activation while increasing the percentage of necrotic cells. The absence of caspase activity confirmed apoptosis-independent cell death. Necrostatin-1 (NEC-1)-mediated necrosome inhibition reduced lysicamine-induced necrosis in KTC-2, suggesting necroptosis induction via a reactive oxygen species (ROS)-independent mechanism. Additionally, in silico analysis predicted lysicamine target proteins, particularly those related to MAPK and TGF-β signaling. Our study demonstrated lysicamine's potential as an antineoplastic compound in ATC cells with a proposed mechanism related to inhibiting AKT activation and inducing cell death.

Tolyporphins-Exotic Tetrapyrrole Pigments in a Cyanobacterium-A Review.

Tolyporphins were discovered some 30 years ago as part of a global search for antineoplastic compounds from cyanobacteria. To date, the culture HT-58-2, comprised of a cyanobacterium-microbial consortium, is the sole known producer of tolyporphins. Eighteen tolyporphins are now known-each is a free base tetrapyrrole macrocycle with a dioxobacteriochlorin (14), oxochlorin (3), or porphyrin (1) chromophore. Each compound displays two, three, or four open β-pyrrole positions and two, one, or zero appended C-glycoside (or -OH or -OAc) groups, respectively; the appended groups form part of a geminal disubstitution motif flanking the oxo moiety in the pyrroline ring. The distinct structures and repertoire of tolyporphins stand alone in the large pigments-of-life family. Efforts to understand the cyanobacterial origin, biosynthetic pathways, structural diversity, physiological roles, and potential pharmacological properties of tolyporphins have attracted a broad spectrum of researchers from diverse scientific areas. The identification of putative biosynthetic gene clusters in the HT-58-2 cyanobacterial genome and accompanying studies suggest a new biosynthetic paradigm in the tetrapyrrole arena. The present review provides a comprehensive treatment of the rich science concerning tolyporphins.

Preclinical pharmacokinetics of a promising antineoplastic prototype piperazine-containing compound (LQFM018) in rats by a new LC-MS/MS bioanalytical method

LQFM018 is a novel antineoplastic prototype, showing an expressive drug-triggered K562 leukemic cells death mechanism, through necroptotic signaling. Due to its promising effect, this study aimed to evaluate the pharmacokinetics of LQFM018 in rats, using a new validated bioanalytical LC-MS/MS-based method. Chromatographic column was an ACE® C18 (100 mm × 4.6 mm, 5 µm) eluted by a mobile phase composed of ammonium acetate 2 mM and formic acid 0.025%:methanol (50:50, v/v), under flow of 1.2 mL/min and injection volume of 3.0 µL. LQFM018 was extracted from rat plasma by a simple liquid–liquid method, using MTBE solvent. Rats were administered intraperitoneally at LQFM018 100 mg/kg dose and blood samples were collect at times of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9 h. Bioanalytical-LC-MS/MS-based method was rapid, high throughput and sensitive with a good linearity ranging from 10 (LLOQ) to 15000 ng/mL, besides precise and accurate, ranging of 0.8–7.3% and 96.8–107.6%, respectively. The prototype LQFM018 was rapid and well absorbed, and highly distributed, apparently due to its high lipid solubility. These features are primordial for an anticancer agent in the treatment of deep tumors, such as bone marrow neoplasms, in which the drug might permeate easily tissue barriers. Also, LQFM018 has demonstrated a high clearance, according to a low t1/2in rats, indicating a relative fast elimination phase related to a possible intense hepatic biotransformation. These information support further studies to establish new understands on pharmacokinetics of promising antineoplastic prototype LQFM018 from preclinical and clinical evaluations.

In Vitro Biological Activity and Lymphoma Cell Growth Inhibition by Selected Mexican Medicinal Plants.

Cancer is a major health problem with significant morbidity and mortality. In addition, plants are a source of metabolites with diverse biological properties, including antitumor potential. In this study, we investigated the in vitro murine lymphoma L5178Y-R cell growth inhibition, human peripheral blood mononuclear cells (PBMC) toxicity and proliferation, and antioxidant, hemolytic, and anti-hemolytic activities of methanol extracts from 15 plants of traditional use in Mexico. Justicia spicigera caused the highest tumor cell growth inhibition with a half maximal inhibitory concentration (IC50) of 29.10 µg/mL and a selectivity index >34.36 compared with those of PBMC, whereas Mimosa tenuiflora showed the highest lymphoproliferative activity from 200 µg/mL compared with that induced by concanavalin A. In addition, M. tenuiflora showed an antioxidant effect (IC50 = 2.86 µg/mL) higher than that of ascorbic acid. Regarding the hemolytic and anti-hemolytic activity, all extracts presented significant anti-hemolytic activity. The extract of J. spicigera is emerging as a possible source of effective antineoplastic compounds.

Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor

Modulation of the CXCL12-CXCR4 signaling axis is of the utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among the different currently available drugs that inhibit CXCR4 activation, motixafortide-a best-in-class antagonist of this GPCR receptor-has exhibited promising results in preclinical studies of pancreatic, breast, and lung cancers. However, detailed information on the interaction mechanism of motixafortide is still lacking. Here, we characterize the motixafortide/CXCR4 and CXCL12/CXCR4 protein complexes by using computational techniques including unbiased all-atom molecular dynamics simulations. Our microsecond-long simulations of the protein systems indicate that the agonist triggers changes associated with active-like GPCR conformations, while the antagonist favors inactive conformations of CXCR4. Detailed ligand-protein analysis indicates the importance of motixafortide's six cationic residues, all of which established charge-charge interactions with acidic CXCR4 residues. Furthermore, two synthetic bulky chemical moieties of motixafortide work in tandem to restrict the conformations of important residues associated with CXCR4 activation. Our results not only elucidate the molecular mechanism by which motixafortide interacts with the CXCR4 receptor and stabilizes its inactive states, but also provide essential information to rationally design CXCR4 inhibitors that preserve the outstanding pharmacological features of motixafortide.

The Phytochemical α-Mangostin Inhibits Cervical Cancer Cell Proliferation and Tumor Growth by Downregulating E6/E7-HPV Oncogenes and KCNH1 Gene Expression.

Cervical cancer is the fourth most common cancer among women worldwide. The main factor associated with the onset and progression of this neoplasia is the human papillomavirus (HPV) infection. The HPV-oncogenes E6 and E7 are critical drivers of cellular transformation, promoting the expression of oncogenes such as KCNH1. The phytochemical α-mangostin (AM) is a potent antineoplastic and antiviral compound. However, its effects on HPV oncogenes and KCNH1 gene expression remain unknown. This study evaluated the effects of AM on cell proliferation, cell cycle distribution and gene expression, including its effects on tumor growth in xenografted mice. AM inhibited cell proliferation in a concentration-dependent manner, being the most sensitive cell lines those with the highest number of HPV16 copies. In addition, AM promoted G1-cell cycle arrest in CaSki cells, while led to cell death in SiHa and HeLa cells. Of interest was the finding of an AM-dependent decreased gene expression of E6, E7 and KCNH1 both in vitro and in vivo, as well as the modulation of cytokine expression, Ki-67, and tumor growth inhibition. On these bases, we suggest that AM represents a good option as an adjuvant for the treatment and prevention of cervical cancer.

A potent ion channel blocker, hydroquinidine, exhibits strong anti-cancer activity on colon, pancreatic, and hepatocellular cancer cells.

Despite recent advances in drug discovery, cancer is still one of the most lethal health problems worldwide. In most cases, standard therapy methods and multi-modal treatments fail, and new therapeutic approaches are required. Ion channels are essential in multiple cellular processes regulating cell division, differentiation, and death. Recent studies on ion-channel modulators emphasize their potential to suppress tumor growth. In that regard, we reasoned that an underinvestigated potassium channel modulator, Hydroquinidine (HQ), may exhibit an anti-carcinogenic activity. HQ's potential as an anti-neoplastic compound was examined using colony formation assay, wound healing assay, soft agar assay, and Annexin-V assay in the colon, pancreatic, and hepatocellular carcinomas. Our findings unveiled a remarkable anti-cancer activity of HQ by decreasing colony-forming ability, migration capacity, tumorigenicity, and proliferation and stimulating cellular death. HQ significantly reduced the formed colonies and tumorigenicity for all cells. It displayed a significant anti-migrative effect on hepatocellular carcinoma cells and promoted apoptosis in pancreatic and liver cancer cells. The altered gene expression profile upon HQ treatment was in accordance with observed cellular effects. Cells incubated with HQ downregulated the genes acting in cell division and survival, whereas the expression level of genes functioning in cell cycle arrest and apoptosis was elevated. Our data indicate HQ's competency to limit cancer growth and suggest its utilization as a novel potent anti-carcinogenic agent. Future studies are necessary to provide new insights into the HQ action mechanism and to evaluate its capacity in in-vivo.

Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways

DNA-targeting agents have a significant clinical use, although toxicity remains an issue that plays against their widespread application. Understanding the mechanism of action and DNA damage response elicited by such compounds might contribute to the improvement of their use in anticancer chemotherapy. In a previous study, our research group characterized a new DNA-targeting agent – pradimicin-IRD. Since DNA-targeting agents and DNA repair are close-related subjects, the present study used in silico-modelling and a transcriptomic approach seeking to characterize the DNA repair pathways activated in HCT 116 cells following pradimicin-IRD treatment. Molecular docking analysis showed pradimicin-IRD as a DNA intercalating agent and a potential inhibitor of DNA-binding proteins. Furthermore, the transcriptomic study highlighted DNA repair functions related to genes modulated by pradimicin-IRD, such as nucleotide excision repair, telomeres maintenance and double-strand break repair. When validating these functions, PCNA protein levels decreased after exposure to pradimicin. Furthermore, molecular docking analysis suggested DNA-pradimicin-PCNA interaction. In addition, hTERT and POLH showed reduced mRNA levels after 6 h of treatment with pradimicin-IRD. Moreover, POLH-deficient cells displayed higher resistance to pradimicin-IRD than POLH-proficient cells and the compound prevented formation of the POLH/DNA complex (molecular docking). Since the modulation of DNA repair genes by pradimicin-IRD is TP53-independent, unlike doxorubicin, dissimilarities between the mechanism of action and the DNA damage response of pradimicin-IRD and doxorubicin open new insights for further studies of pradimicin-IRD as a new antineoplastic compound.

Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction

Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) exvivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells.

Chemotherapy-induced neuropathic pain is a debilitating and dose-limiting side effect. Oxaliplatin is a third-generation platinum and antineoplastic compound that is commonly used to treat colorectal cancer and commonly yields neuropathic side effects. Available drugs such as duloxetine provide only modest benefits against oxaliplatin-induced neuropathy. A particularly disruptive symptom of oxaliplatin is painful cold sensitivity, known as cold allodynia. Previous studies of the Conus regius peptide, RgIA, and its analogs have demonstrated relief from oxaliplatin-induced cold allodynia, yielding improvement that persists even after treatment cessation. Moreover, underlying inflammatory and neuronal protection were shown at the cellular level in chronic constriction nerve injury models, consistent with disease-modifying effects. Despite these promising preclinical outcomes, the underlying molecular mechanism of action of RgIA4 remains an area of active investigation. This study aimed to determine the necessity of the α9 nAChR subunit and potential T-cell mechanisms in RgIA4 efficacy against acute oxaliplatin-induced cold allodynia. A single dose of oxaliplatin (10 mg/kg) was utilized followed by four daily doses of RgIA4. Subcutaneous administration of RgIA4 (40 µg/kg) prevented cold allodynia in wildtype mice but not in mice lacking the α9 nAChR-encoding gene, chrna9. RgIA4 also failed to reverse allodynia in mice depleted of CD3+ T-cells. In wildtype mice treated with oxaliplatin, quantitated circulating T-cells remained unaffected by RgIA4. Together, these results show that RgIA4 requires both chrna9 and CD3+ T-cells to exert its protective effects against acute cold-allodynia produced by oxaliplatin.

A Review on anticancer potential of Nitric Oxide

Nitrous oxide (N2O; laughing gas) is clinically used as a safe anesthetic (dentistry, ambulance, childbirth) and is appreciated for its anti-anxiety effect. Nitrous oxide (N2O) is a free radical gas that performs various physiological and pathological processes in the body. NO is produced by different enzymatic pathways and plays a role in homeostasis. Over the past years, NO has emerged as a molecule of interest in many ailments including cancer. But its role in cancer is still controversy. It can display dose-dependent anticancer therapy on the one hand and induce pro-cancer properties on the other hand. But as compared to conventional treatments, NO proved better tumor cell resistance. This review mentions the dichotomous nature of NO that may encourage future research assessing the role of NO in cancer prevention and treatment either as a single agent or in combination with other antineoplastic compounds.

1668P Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction

Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with specific genomic and pathological characteristics. Although some 30 anti-neoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed. Several patient-derived tumor models have been proposed to serve as therapeutic prediction tools. However, the lack of tumor microenvironment considerations and time-consuming procedures make their clinical utility limited. Cells were recovered from newly resected breast tumors as whole-tumor cell cultures (WTCs). Immunohistochemistry, flow cytometry, DNA- and RNA- sequencing were performed to ensure the WTCs recapitulate the biology of original tumors. A broad range of clinically relevant drugs was tested on the WTCs. Cell viability assay, real-time imaging tool, transcriptomic analysis, and panel gene-expression analysis were carried out to investigate the model's predictive value and clinical relevance. A separate validation study was also carried out to compare WTC-based test results and patients’ clinical responses in neoadjuvant treatment settings. We generated WTCs with a high success rate (±90%) for all subtypes of breast tumors. The hormone receptors, Ki67, HER2 status, tumor microenvironment interactions, mutational signatures, and gene-expression profiles were well-retained in the WTCs. We observed strong clinical relevance and predictive values in WTCs from the drug-profiling data by calculating drug sensitivity scores (DSS) in combination with gene-expression analyses. The WTC-based testing results and patient clinical responses toward standard neoadjuvant therapies also showed good concordance for the first 15 enrolled BC patients in the validation study. The WTC represents the original tumor characteristics to a large extent and allows us to accomplish personalized drug testing within 10-days, highlighting its potential for individualized BC therapy. Coupled with genomic and transcriptomic analyses, WTC-based testing can also help stratify specific BC patient groups for assignment into appropriate clinical trials and validate potential biomarkers.

Biological Activities of Seven Medicinal Plants Used in Chiapas, Mexico.

Seven medicinal plants from Chiapas, Mexico, used by Native Americans were analyzed, aiming to improve the understanding of their medicinal properties through the evaluation of various biological activities, i.e., bactericidal, antioxidant, α-glucosidase inhibition, and toxicity, to provide a scientific basis for the management of infectious and hyperglycemic diseases in the Mexican southeast. Plant extracts were obtained from Cordia dodecandra, Gaultheria odorata, Heliotropium angiospermum, Justicia spicigera, Leucaena collinsii spp. collinsii, Tagetes nelsonii, and Talisia oliviformis through maceration techniques using methanol and chloroform (1:1). Minimum Inhibitory Concentration (MIC) was employed to determine the antibacterial activity against Staphylococcus aureus, Enterobacter faecalis, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeuroginosa. The antiradical/antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays and antihemolytic activity using the 2,2’-Azobis(2-amidinopropane) dihydrochloride radical (APPH). The anti-α-glucosidase activity was evaluated in vitro through the chromogenic PNPG assay. The toxicity was assessed using the brine shrimp lethality assay. The highest antimicrobial activity was displayed by T. nelsonii, mainly against E. faecalis and P. aeuroginosa. The extracts of L. collinsii, J. spicigera, and T. nelsonii possess antioxidant properties with EC50 < 50 μg/mL. J. spicigera and T. nelsonii extracts showed the highest antihemolytic activity with IC50 < 14 μg/mL. T. nelsonii exhibited a remarkable inhibitor effect on the α-glucosidase enzyme and the greatest toxic effect on Artemia salina with IC50 = 193 ± 20 μg/mL and LD50 = 14 ± 1 μg/mL, respectively. According to our results, G. odorata, J. spicigera, T. nelsonii, and T. oliviformis extracts contained active antimicrobial compounds. At the same time, T. nelsonii stands to be a possible source of effective antineoplastic and antihyperglycemic compounds.

Marine Antineoplastic Templates: Clinical trials (I-III) and Motifs Carried via Antibodies to Target Specific Cancerous Tissues

Aquatic environment is one of the important sources of active agents that own diverse biological properties. Metabolites from these sources are considered as alternate source to meet the mandate for effective medicines. Despite notable developments in cancer managing and/or treatment in the past years, there remains a vital requirement for innovative agents and/or innovating approaches to treat resistant and solid tumours. However, in the recent era there are new technological innovations in the elucidation of the structures, the semi-synthetic and synthetic approaches of the new antineoplastic compounds. Biological assays enable isolation and clinical evaluation of numerous scaffolds from the marine environment. This review gives a general summary of some anti-cancer agents with a brief description of their mechanisms of action. It sheds a view to the approved drugs, the potent scaffolds that newly modulated as antibody-drug conjugates, and the drug-candidates under clinical phases (I-III) with their status.

Abstract 4060: Identification of anti-neoplastic compounds on a triple negative breast cancer cell line from T. violacea

Abstract Background: The incidence of Invasive triple negative breast cancer (TNBC) is higher than average in South Africa, with 90% of patients being Black South Africans. Current treatments for breast cancer are associated with severe side effects. Additionally, TNBC is resistant to hormone therapy commonly used to treat other forms of breast cancer. Tulbaghia violacea, a plant native to Southern Africa, is a medicinal herb used in traditional medicine. This study aims to establish the impact of water soluble extracts from T. violacea on TNBC cancer cell lines and identify any anti-cancer compounds present in this extract. Methods: Following the determination of the IC50 value for this extract. The anti-proliferative and anti-metastatic activities of the extract on the TNBC cell line were determined using scratch assays and cell invasion and migration assays, performed using real time cell analysis. The pro-apoptotic action of the extract on the TNBC cell line was determined using flow cytometry cell death assays. Once the anti-cancer activity of the extract was confirmed, the composition of the extract was determined in order to establish what known or possible anti-cancer compounds are present within it. This was performed using gas chromatography-mass spectroscopy (GC-MS). The structure of these identified compounds was then confirmed using Nuclear Magnetic Resonance (NMR). Results: The IC50 value for the T. violacea water soluble extract against MDA MB 231 cells was determined to be ~350 µg/mL. The extract was also shown to have anti migration and invasion as well as pro-apoptotic effects on these cells. Fourteen known anti-cancer compounds were identified in this water soluble extract. In addition to this multiple other compounds were shown to also be present in the extract. Discussion: The water soluble T. violacea leaf extract has cytotoxic effects and the ability to inhibit proliferation and metastasis in a TNBC cell line. The identification of fourteen compounds with known anti-cancer activity may explain the effects this extract has on these TNBC cells, however, the contribution made by any of the other compounds to this activity remains to be determined. Conclusion: These findings suggest that one or more of the compounds present in T. violacea may serve as lead compounds for the development of new treatments for TNBC. Citation Format: Zodwa Dlamini, Clement Penny, Rodney Hull, Mohammed Alouna. Identification of anti-neoplastic compounds on a triple negative breast cancer cell line from T. violacea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4060.

Development of α-Tocopherol Succinate-Based Nanostructured Lipid Carriers for Delivery of Paclitaxel.

The management of retinoblastoma (RB) involves the use of invasive treatment regimens. Paclitaxel (PTX), an effective antineoplastic compound used in the treatment of a wide range of malignant tumors, poses treatment challenges due to systemic toxicity, rapid elimination, and development of resistance. The goal of this work was to develop PTX-loaded, α-tocopherol succinate (αTS)-based, nanostructured lipid carrier (NLCs; αTS-PTX-NLC) and PEGylated αTS-PTX-NLC (αTS-PTX-PEG-NLC) to improve ocular bioavailability. The hot homogenization method was used to prepare the NLCs, and repeated measures ANOVA analysis was used for formulation optimization. αTS-PTX-NLC and αTS-PTX-PEG-NLC had a mean particle size, polydispersity index and zeta potential of 186.2 ± 3.9 nm, 0.17 ± 0.03, −33.2 ± 1.3 mV and 96.2 ± 3.9 nm, 0.27 ± 0.03, −39.15 ± 3.2 mV, respectively. The assay and entrapment efficiency of both formulations was >95.0%. The NLC exhibited a spherical shape, as seen from TEM images. Sterilized (autoclaved) formulations were stable for up to 60 days (last time point checked) under refrigerated conditions. PTX-NLC formulations exhibited an initial burst release and 40% drug release, overall, in 48 h. The formulations exhibited desirable physicochemical properties and could lead to an effective therapeutic option in the management of RB.