Cancer Cells Research Articles

Precision Cancer Therapy Enabled Anti-Epidermal Growth Factor Receptor-Conjugated Manganese Core Phthalocyanine Bismuth Nanocomposite for Dual Imaging-Guided Breast Cancer Treatment

Cancer remains a formidable global health challenge, demanding the exploration of innovative treatment modalities with minimized side effects. One promising avenue involves the synergistic integration of targeted photothermal/photodynamic therapy (PTT/PDT), utilizing specially designed functional nanomaterials for precise cancer diagnosis and treatment. This study introduces a composite biomaterial, anti-epidermal growth factor receptor-conjugated manganese core phthalocyanine bismuth (anti-EGFR-MPB), synthesized for precise cancer imaging and treatment. The biomaterial, synthesized via a solvothermal process, effectively treats and images breast cancer in mouse models. Its biomimetic design targets cancer cells precisely, with dual imaging for real-time monitoring. The biomimetic design of the composite enables precise targeting of cancer cells, whereas the dual imaging allows for real-time visualization and monitoring of the treatment. In vivo examinations confirm substantial damage to tumor tissues with no recurrence following 808-nm laser irradiation. The composite shows strong fluorescence/photoacoustic imaging (PAI) contrast, aiding malignancy detection. Biological assays and histological analyses confirmed the efficacy of the nanocomposite in inducing apoptosis in cancer cells. The integrated targeted dual image-guided phototherapy offered by this composite substantially enhances the precision and efficacy of cancer therapy, achieving an impressive photothermal efficiency of ~33.8%. Our findings demonstrate the utility of the anti-EGFR-MPB nanocomposite for both in vitro and in vivo photoacoustic image-guided PTT and PDT. The optimal treatment strategy for triple-negative breast cancer is found to be the use of 250 μg/ml of nanocomposite irradiated with 1.0 W/cm 2 808-nm laser for 7 min.

Adipocytes reprogram the proteome of breast cancer cells in organotypic three-dimensional cell cultures.

While epidemiological evidence has long linked obesity with an increased risk of breast cancer, the intricate interactions between adipocytes and cancer cells within the tumor microenvironment remain largely uncharted territory. The use of organotypic three-dimensional (3D) cell cultures that more accurately mimic the spatial architecture of tumors represents an innovative approach to this complex issue. In the present study, we investigated the effects of adipocytes on the proteome of Hs578t breast cancer cells cultured in a 3D microenvironment. Using different treatments, we rigorously optimized the experimental conditions to induce the optimal differentiation of 3T3-L1 fibroblasts into mature adipocytes. Then, we grow the Hs578t cells in a simulated microenvironment using an on-top model for organotypic 3D cultures. Our data showed that cancer cells formed 3D stellate-like architectures when grown over an extracellular matrix proteins-enriched scaffold for 48h. Proteomic profiling using LC-MS/MS mass spectrometry of Hs578t cells grown in 3D conditions with or without the adipocyte-enriched culture discovered 916 unique proteins. Of these, 605 showed no significant changes in abundance, whereas 87 proteins were significantly upregulated and 224 downregulated after interaction with fat cells (p < 0.05, FC > 2.0). Bioinformatic analysis of upregulated proteins indicated that the most enriched GO terms and molecular functions were related to lipids transport, cell differentiation, hypoxia response, and cell junctions. In addition, several modulated proteins have been previously associated with breast cancer progression. Interestingly, lipid transport proteins, including PITPNM2, ATP2C1, ABCA12, HDLBP, and APOB, showed perturbations in their expression, which were also associated with low overall survival in breast cancer patients. Functional studies showed that the knockdown of apolipoprotein B (APOB) expression in Hs578t cells reduced the size of 3D cellular structures. Moreover, APOB-knocked cells cocultured with adipocytes for 48h exhibited a significant decrease of intracellular lipids, whereas an increase in the adipocytes was found. Our results indicate that the 3D microenvironment and the adipocytes crosstalk reprogram the proteome of breast cancer cells. These data help us understand the environmental effects in gene expression and contribute to discovering novel tumor proteins with potential intervention in breast cancer therapy.

Survival Resonances during Fractional Killing of Cell Populations

Fractional killing in response to drugs is a hallmark of nongenetic cellular heterogeneity. Yet how individual lineages evade drug treatment, as observed in bacteria and cancer cells, is not quantitatively understood. We study a stochastic population model with age-dependent division and death rates, allowing for persistence. In periodic drug environments, we discover peaks in the survival probabilities at division or death times that are multiples of the environment duration. The survival resonances are unseen in unstructured populations and are amplified by persistence. Published by the American Physical Society 2024

Flavonoids as Chemosensitizers in Leukemias.

Flavonoids, a diverse group of natural compounds abundant in plants, fruits, and seeds, are not only responsible for the vibrant colors, fragrances, and flavors found in nature but also possess significant health benefits. Representing a secondary metabolite, these phytonutrients contribute to overall well-being. They have garnered considerable interest due to their diverse biological roles, encompassing antioxidant, anti-inflammatory, and anticancer properties. Flavonoids exert anticancer properties by interfering with different signaling pathways and molecules. Also, they have been demonstrated to exert chemosensitization features, where flavonoids may enhance the effectiveness of chemotherapy, and hold promise for improving cancer treatment outcomes as they have been discovered to make cancer cells more responsive to treatment. Understanding their influence on the regulation of cellular signaling provides a foundation for exploring their potential in combination with different chemotherapy agents and their possible single use for cancer treatment. Besides, they are believed to present a cost-effective approach to cancer therapeutics with possible implications for reducing the side effects of the current chemotherapy regimens, which can be a great therapeutic strategy for treating cancer types, including leukemia. This chapter explores potential approaches for creating anticancer treatments, focusing on leukemia, through integrating flavonoid nutraceuticals with traditional chemotherapy agents.

Smart Mesoporous Silica Nanoparticles Loading Curcumin Inhibit Liver Cancer.

Curcumin (CUR) as one of the natural edible pigments is approved by the World Health Organization due to its nontoxic and anticancer effect. However, the utility of CUR is restricted due to its low oral bioavailability. Nanoparticle drug delivery systems like mesoporous silica nanoparticles (MSNs) have been extensively used due to their high specific surface area, high loading rate, and ease of modification. This study developed lactobionic acid (LA)-modified carboxymethyl chitosan (CMCS)-coated MSNs to deliver CUR specifically targeting hepatocellular carcinoma. Among these nanoparticles, LA targets liver cancer cells. CMCS utilizes pH-responsive release of CUR. The LA-CMCS-MSN@CUR (MSN@CUR) were evaluated using several methods, including Fourier transform infrared spectroscopy, transmission electron microscopy, and zeta potential measurements. Liver cellular uptake of MSN@CUR depends on a specific LA receptor-mediated endocytosis mechanism. Additionally, MSN@CUR performed with a better antitumor effect than Cur in H22 orthotopic transplantation of liver cancer and H22 solid tumor mouse models. Treatment with MSN@CUR significantly reduced the protein of VEGF, p-PI3K, and AKT, increased the protein of caspases 3 and 8, ultimately inhibited tumor migration, and promoted apoptosis. This study provides a new path for delivery of natural active ingredients with excellent bioavailability in the antitumor field.

A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies

Abstract T-cell activation is a multistep process requiring T-cell receptor engagement by peptide–MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell–mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell–mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti–programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti–programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen–targeted anti-CD3 (Signal 1) T-cell engagers.

Chemical Profile of Kumquat (Citrus japonica var. margarita) Essential Oil, In Vitro Digestion, and Biological Activity

Kumquat is one of the smallest citrus fruits (from the Rutaceae family), and its essential oil’s biological effects have not yet been sufficiently researched, in contrast to the essential oils of its relatives. Therefore, the aim of this large-scale study was to investigate the chemical profile of kumquat essential oils (KEOs) isolated by microwave-assisted distillation (MAD) and Clevenger hydrodistillation using GC-MS analysis. To test the bioaccessibility of their bioactive components, in vitro digestion with commercially available enzymes was performed. The final step of this research was to test their cytotoxic activity against a cervical cancer cell line (HeLa), a human colon cancer cell line (HCT116), a human osteosarcoma cell line (U2OS), and a healthy cell line (RPE1). Two methods were used to test the antioxidant activity: DPPH (2,2-diphenyl-1-picrylhydrazyl) and ORAC (oxygen radical absorbance capacity). The antibacterial activity was tested in relation to the growth and adhesion of Escherichia coli and Staphylococcus aureus on a polystyrene surface. The GC-MS analysis showed that the major compound in both kumquat essential oils was limonene, which was stable before and after in vitro digestion (&gt;90%). The results showed that the cytotoxic activity of the KEOs in all three cancer cell lines tested was IC50 1–2 mg/mL, and in the healthy cell line (RPE1), the IC50 value was above 4 mg/mL. The antibacterial activity of the KEOs obtained after MAD and Clevenger hydrodistillation was 4 mg/mL against E. coli and 1 mg/mL against S. aureus. The KEOs after MAD and Clevenger hydrodistillation reduced the adhesion of E. coli by more than 1 log, while there was no statistically significant effect on the adhesion of S. aureus to the polystyrene surface. Both KEOs exhibited comparable levels of antioxidant activity using both methods tested, with IC50 values of 855.25 ± 26.02 μg/mL (after MAD) and 929.41 ± 101.57 μg/mL (after Clevenger hydrodistillation) for DPPH activity and 4839.09 ± 91.99 μmol TE/g of EO (after MAD) and 4928.78 ± 275.67 μmol TE/g of EO (after Clevenger hydrodistillation) for ORAC. The results obtained show possible future applications in various fields (e.g., in the food, pharmaceutical, cosmetic, and agricultural industries).

A Rationally Designed Azobenzene Photoswitch for DNA G‐Quadruplex Regulation in Live Cells

AbstractG‐quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4‐specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light‐responsive G4‐binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4‐associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain, Q‐Azo4F‐C, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its trans and cis configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25‐fold reversible cytotoxic activity. Immunostaining conducted with the structure‐specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo‐driven reversible regulation of G4 structures in lung cancer cells by Q‐Azo4F‐C. Our findings highlight the potential of light‐responsive G4‐binders in advancing precision cancer therapy through dynamic control of G4‐mediated pathways.

New series of 4,6-diaryl pyrimidines: facile synthesis and antiproliferative activity as dual EGFR/VEGFR-2 inhibitors

IntroductionWe developed and produced a new series of 4,6-diaryl-pyrimidines 9–29 as antiproliferative agents targeting EGFR/VEGFR-2.MethodsThe antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines in vitro.Results and DiscussionCompounds 14, 17, 19, 22, 25, and 29 demonstrated the greatest potency among the derivatives, with GI50 values between 22 and 33 nM; compounds 22 and 29 exhibited the highest potency, with GI50 values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds 22 and 29 functioned as dual inhibitors. Moreover, 22 and 29 can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds 22 and 29 were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound 22 but only 80% with compound 29. The docking study showed that compounds 22 and 29 had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity.

The radiosensitivity of niraparib tosylate to esophageal squamous cell carcinoma is stronger under hypoxia and higher-pressure conditions

Background: Radiotherapy is an effective method for esophageal squamous cell carcinoma (ESCC) treatment show reduced effectiveness in long-term due to reduced sensitivity of cancer cells to radiotherapy. Niraparib tosylate, a poly ADP-ribose polymerase (PARP) inhibitor may enhance the radiosensitivity of these cells. Hence, the present study was aimed to study the effects of niraparib tosylate on ESCC proliferation, apoptosis and cell cycle along with radiosensitivity enhancement efficiency. Materials and methods: ESCC cell lines, KYSE-30 were subjected to niraparib tosylate or irradiation treatments or combination of both. CCK8 and colony formation assays were performed to monitor cell growth status. Cell cycle and apoptosis level were investigated through flow cytometry. The expressions of targeted genes were detected at protein levels by western blot. Besides, xenografts were successfully established in immunocompromised mice. Student’s t-test was used to compare data and P &lt; 0.05 was considered statistically significant. Results: Treatment with niraparib tosylate showed G2/M cycle arrest and apoptosis in KYSE-30 cells and the rate was observed to be more significant with combination therapy. These effects were further strengthened when cells were cultured under hypoxia and high atmospheric pressure. An enhanced susceptibility to radiotherapy was observed with niraparib tosylate combination. The homologous recombination related regulator, Rad51, showed remarkable upregulation in cancer cells exposed to combination of drug-radiation treatment. The tumor burden was also relieved in xenograft mouse models with combination of drug-radiation treatment, indicating the potential of niraparib tosylate use clinical cancer therapy. Conclusion: From the results, a novel function of niraparib tosylate can be established, impairing DNA damage repair efficiency to increase the susceptibility of ESCC to radiotherapy, resulting in cell apoptosis and G2/M cycle arrest in vitro and in vivo.

Hydrogen Sulfide‐Triggered Artificial DNAzyme Switches for Precise Manipulation of Cellular Functions

AbstractThe development of synthetic molecular tools responsive to biological cues is crucial for advancing targeted cellular regulation. A significant challenge is the regulation of cellular processes in response to gaseous signaling molecules such as hydrogen sulfide (H2S). To address this, we present the design of Gas signaling molecule‐Responsive Artificial DNAzyme‐based Switches (GRAS) to manipulate cellular functions via H2S‐sensitive synthetic DNAzymes. By incorporating stimuli‐responsive moieties to the phosphorothioate backbone, DNAzymes are strategically designed with H2S‐responsive azide groups at cofactor binding locations within the catalytic core region. These modifications enable their activation through H2S‐reducing decaging, thereby initiating substrate cleavage activity. Our approach allows for the flexible customization of various DNAzymes to regulate distinct cellular processes in diverse scenarios. Intracellularly, the enzymatic activity of GRAS promotes H2S‐induced cleavage of specific mRNA sequences, enabling targeted gene silencing and inducing apoptosis in cancer cells. Moreover, integrating GRAS with dynamic DNA assembly allows for grafting these functional switches onto cell surface receptors, facilitating H2S‐triggered receptor dimerization. This extracellular activation transmits signals intracellularly to regulate cellular behaviors such as migration and proliferation. Collectively, synthetic switches are capable of rewiring cellular functions in response to gaseous cues, offering a promising avenue for advanced targeted cellular engineering.

Role of the basic leucine zipper transcription factor BATF2 in modulating immune responses and inflammation in health and disease.

Basic leucine zipper transcription factor ATF-like 2 (BATF2) is a transcription factor that is known to exhibit tumor-suppressive activity in cancer cells. Within recent years, however, BATF2 has also emerged as an important transcriptional regulator of the immune system. Through its immunomodulatory function, BATF2 has been implicated in a variety of (patho)physiological processes, including host defense against infection, anti-tumor immunity, and maintenance of tissue inflammatory homeostasis. Below, we discuss recent literature that has provided insight into the role of BATF2 as a transcriptional regulator of immune responses in health and disease, including the cell types that express BATF2, the different diseases in which the immunomodulatory effects of BATF2 have been shown to play a role, and the molecular mechanisms through which BATF2 is thought to exert those effects. In doing so, we highlight that the immunological effects of BATF2 are highly context-dependent, and we point out overlap between the mechanisms of action of BATF2 in infectious disease and non-infectious disease. We also discuss areas of interest for future research, the clinical relevance of better understanding BATF2 function, and potential strategies for therapeutic modulation of BATF2.

Thieno[3,2-b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode.

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2-b]pyridine scaffold. The weak interaction of the thieno[3,2-b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome-wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP-competitive but not ATP-mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2-b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2-b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs.

AI-powered precision: breast carcinoma diagnosis through digital proliferation index (Ki-67) assessment in pathological anatomy

PurposeThe primary objective of the study is to enhance the accuracy and efficiency of assessing the proliferation index in cancer cells, specifically focusing on the role of Ki-67. The purpose is to address the limitations of traditional visual assessments conducted by pathologists by integrating AI technologies, particularly deep learning. By accurately computing the percentage of Ki-67-labeled cells, the research aims to streamline the diagnostic process, reduce subjectivity and contribute to the advancement of diagnostic precision in pathological anatomy.Design/methodology/approachThe research employs a methodological approach that integrates Ki-67, a non-histone nuclear protein, as a vital biomarker for assessing the proliferative status of cancer cells. Given the challenges associated with traditional visual assessments by pathologists, including inter- and intra-observer variability and time-consuming efforts, the study adopts a novel methodology leveraging artificial intelligence (AI) solutions. Deep learning is applied to precisely calculate the percentage of Ki-67-labeled cells. The process involves pathologists delineating the tumor area at x40 magnification, enabling the segmentation of various cell types (positive, negative and tumor-infiltrating lymphocytes). The subsequent percentage calculation enhances efficiency and minimizes subjectivity in the diagnostic process.FindingsDespite inherent errors, the research findings indicate that the model surpasses existing benchmarks, showcasing superior accuracy in terms of average error measurement. The comparison with diverse datasets and benchmarking against pathologists’ diagnoses contributes empirical evidence to support the effectiveness of the AI-based model in accurately computing the percentage of Ki-67-labeled cells. These findings signify a noteworthy advancement in diagnostic methodologies and reinforce the potential of AI technologies in improving the precision of cancer diagnostics within the realm of pathological anatomy.Originality/valueThe research contributes to the field by introducing an innovative approach that combines Ki-67 as a biomarker and AI technologies for improved diagnostic precision. The originality lies in the utilization of deep learning to calculate the percentage of labeled cells, mitigating the challenges associated with manual assessments. The validation of the model against diverse datasets and benchmarking against pathologists’ diagnoses demonstrates its superior accuracy, highlighting the value of integrating AI in pathological anatomy for enhanced diagnostic outcomes. The study represents a significant stride in original research, offering novel insights and methodologies in the pursuit of more precise cancer diagnostics.

Systemic hormone therapy after breast and gynecological cancers: an Italian expert group consensus opinion.

The specific Italian Group of Study of the Menopause formulated a consensus opinion on the use of estrogen therapy (ET) or combined estro-progestin hormone therapy (HT) after breast and gynecological cancers. This consensus is based on the risk of recurrence of the specific cancer during ET/HT, the presence of steroid receptors in cancer cells, the use of adjuvant hormone therapies and data on the use of ET/HT after cancer. The following positions were reached. ET/HT can be used after vulvar cancers and melanoma, but with great caution after the rare adenocarcinomas. ET/HT can be used after cervical cancer, but ET should be used with caution after adenocarcinomas. ET/HT can be used after International Federation of Obstetrics and Gynecology (FIGO) stage I-II estrogen-dependent endometrial cancers, except in Black women, and can probably be used after estrogen-independent endometrial cancers. ET/HT cannot be administered or should be used with great caution after most uterine sarcomas. ET/HT can probably be used after ovarian neoplasms except for granulosa cell tumors, and with great caution after low-grade serous ovarian carcinoma and serous borderline ovarian tumors. ET/HT can be used with great caution in women after estrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer and is probably allowed after ER/PR-negative breast cancer.

Thieno[3,2‐b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2‐b]pyridine scaffold. The weak interaction of the thieno[3,2‐b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome‐wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP‐competitive but not ATP‐mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2‐b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2‐b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs.

Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers.

RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRASG12C inhibitor breaks the "undruggable" curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRASG12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.

Fibrin Nanoparticles as a Promising Anti-cancer Activity on MCF-7 Cells

Background: Drug delivery methods based on nanoparticles have shown promise in the treatment of cancer. The nanoparticles (NPs) have a cytotoxicity effect on cancer cells. Objectives: This study aimed to evaluate the effect of fibrin nanoparticles (FNPs) on breast cancer cells. Methods: MCF-7 cell lines were treated with 100 µg/mL of FNP for 5 days. On day five, gene and protein expression were evaluated to determine the anti-cancer effects of the FNPs. Results: BCL2, an anti-apoptotic (BCL2) and angiogenic (VEGF) genes and proteins were downregulated in the FNP treatment in comparison with control cells. Conclusions: The study's findings indicate that FNPs considerably reduce anti-apoptotic and angiogenic gene expression in human breast cancer cells.

Host-Guest Adduct as a Stimuli-Responsive Prodrug: Enzyme-Triggered Self-Assembly Process of a Short Peptide Within Mitochondria to Induce Cell Apoptosis.

To address the issue of nonspecific biodistribution of a chemotherapeutic drug, stable [2]pseudorotaxane complexes (PK@CAOPP and PR@CAOPP) are used to demonstrate a proof of concept. Cationic -PPh3 + moiety in CAOPP allows specific localization of the PK@CAOPP/ PR@CAOPP in the mitochondrial membrane (MM). Electrostatic interaction between the cationic LysinePK or ArgininePR moiety and the negatively charged phosphoesterCAOPP functionality in CAOPP favours strong adduct formation. The ALP-induced hydrolytic cleavage of the phosphoester moiety in cancer cells triggers dephosphorylation and releases PK/ PR moiety from PK@CAOPP/PR@CAOPP. PK or PR, derived from the Phe-Phe dipeptide, formed fibril-like molecular aggregates in the MM to induce dysfunction, depolarization, ROS generation and apoptotic MCF7 cell death. Such phenomena were not observed in ALP-negative HEK293 normal cells. These propositions were confirmed through control studies using NBDK and PE, other guest molecules. Smaller size and inclusion of the short peptides (PK or PR) within the hydrophobic interior of CAOPP, were attributed to their stability in blood serum. Thus, we have demonstrated the use of supramolecular adducts as a potential therapeutic option for treating cancer cells without affecting healthy cells. The efficacy was also established with an in-vivo MCF7 tumour xenograft model using Balb/c nude mice.

Predicting drug resistance.

A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.