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1.
Crit Rev Oncol Hematol ; 201: 104417, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38901639

ABSTRACT

Triple-negative breast carcinoma (TNBC) is one of the most challenging subtypes of breast carcinoma and it has very limited therapeutic options as it is highly aggressive. The prognostic biomarkers are crucial for early diagnosis of the tumor, it also helps in anticipating the trajectory of the illness and optimizing the therapy options. Several therapeutic biomarkers are being used. Among them, the next-generation biomarkers that include Circulating tumor (ct) DNA, glycogen, lipid, and exosome biomarkers provide intriguing opportunities for enhancing the prognosis of TNBC. Lipid and glycogen biomarkers serve as essential details on the development of the tumor along with the efficacy of the treatment, as it exhibits metabolic alteration linked to TNBC. Several types of biomarkers have predictive abilities in TNBC. Elevated levels are associated with worse outcomes. ctDNA being a noninvasive biomarker reveals the genetic composition of the tumor, as well as helps to monitor the progression of the disease. Traditional therapies are ineffective in TNBC due to a lack of receptors, targeted drug delivery provides a tailored approach to overcome drug resistance and site-specific action by minimizing the side effects in TNBC treatment. This enhances therapeutic outcomes against the aggressive nature of breast cancer. This paper includes all the recent biomarkers which has been researched so far in TNBC and the state of art for TNBC which is explored.

2.
J Cell Physiol ; 239(4): e31203, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38345361

ABSTRACT

Triple negative breast cancers (TNBC) are an aggressive molecular subtype of breast carcinoma (BC) identified by the lack of receptor expression for estrogen, progesterone, & human epidermal growth factor receptor-2. Lack of tangible drug targets warrants further research in TNBC. LIV1, is a zinc (Zn) transporter known to be overexpressed in few cancer types including BCs. Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN-LIV1A for treatment of TNBC patients. Though LIV1 also has a role in modulating immune cells by its differential transport of Zn, a correlation between the tumor cell expression of LIV1 and immune cell infiltrations were scantily reported. Further adequate baseline data on LIV1 expression in other populations have not been documented. Our objective was to screen a large Indian cohort of TNBC patient samples for LIV1, categorize the immune cell infiltration using CD4/CD8 expression and correlate the findings with therapy outcomes. Further, we also investigated for LIV1 expression in matched samples of primary & secondary tumors; pre & postchemotherapy in TNBC patients. Results showed an elevated expression of LIV1 in TNBC samples as compared to adjacent normal, the mean Q scores being 183.06 ± 6.39 and 120.78 ± 7.37 (p < 0.0001), respectively. Similarly, LIV1 levels were elevated in secondary tumors than primary & in patient samples postchemotherapy as compared to naïve. In the TNBC cohort, using automated method, cell morphology parameters were computed and analysis showed LIV1 levels were elevated in grade 3 TNBC samples presenting with altered cell morphology parameters namely cell size, cell perimeter, & nucleus size. Thus indicating LIV1 expressing TNBC samples portrayed an aggressive phenotype. Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Carrier Proteins , Phenotype , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/metabolism , Cell Line, Tumor , Lymphocytes, Tumor-Infiltrating/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology
3.
Appl Biochem Biotechnol ; 196(1): 382-399, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37133677

ABSTRACT

Inorganic nanoparticles (NPs) have played an important role as nano-drug delivery systems during cancer therapy in recent years. These NPs can carry cancer therapeutic agents. Due to this, they are considered a promising ancillary to traditional cancer therapies. Among inorganic NPs, Zinc Oxide (ZnO) NPs have been extensively utilized in cellular imaging, gene/drug delivery, anti-microbial, and anti-cancerous applications. In this study, a rapid and cost-effective method was used to synthesize Nat-ZnO NPs using the floral extract of the Nyctanthes arbor-tristis (Nat) plant. Nat-ZnO NPs were physicochemically characterized and tested further on in vitro cancer models. The average hydrodynamic diameter (Zaverage) and the net surface charge of Nat-ZnO NPs were 372.5 ± 70.38 d.nm and -7.03 ± 0.55 mV, respectively. Nat-ZnO NPs exhibited a crystalline nature. HR-TEM analysis showed the triangular shape of NPs. Furthermore, Nat-ZnO NPs were also found to be biocompatible and hemocompatible when tested on mouse fibroblast cells and RBCs. Later, the anti-cancer activity of Nat-ZnO NPs was tested on lung and cervical cancer cells. These NPs displayed potent anti-cancer activity and induced programmed cell death in cancer cells.


Subject(s)
Metal Nanoparticles , Nanoparticles , Zinc Oxide , Animals , Mice , Zinc Oxide/pharmacology , Zinc Oxide/chemistry , Anti-Bacterial Agents/pharmacology , Metal Nanoparticles/chemistry , Microbial Sensitivity Tests , Flowers , Plant Extracts/pharmacology , Plant Extracts/chemistry
4.
Appl Biochem Biotechnol ; 196(2): 1058-1078, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37318689

ABSTRACT

Metal/Metal Oxide nanoparticles (M/MO NPs) exhibit potential biomedical applications due to their tunable physicochemical properties. Recently, the biogenic synthesis of M/MO NPs has gained massive attention due to their economical and eco-friendly nature. In the present study, Nyctanthes arbor-tristis (Nat) flower extract-derived Zinc Ferrite NPs (Nat-ZnFe2O4 NPs) were synthesized and physicochemically characterized by FTIR, XRD, FE-SEM, DLS, and other instruments to study their crystallinity, size, shape, net charge, presence of phytocompounds on NP's surface and several other features. The average particle size of Nat-ZnFe2O4 NPs was approx. 25.87 ± 5.67 nm. XRD results showed the crystalline nature of Nat-ZnFe2O4 NPs. The net surface charge on NPs was -13.28 ± 7.18 mV. When tested on mouse fibroblasts and human RBCs, these NPs were biocompatible and hemocompatible. Later, these Nat-ZnFe2O4 NPs exhibited potent anti-neoplastic activity against pancreatic, lung, and cervical cancer cells. In addition, NPs induced apoptosis in tested cancer cells through ROS generation. These in vitro studies confirmed that Nat-ZnFe2O4 NPs could be used for cancer therapy. Moreover, further studies are recommended on ex vivo platforms for future clinical applications.


Subject(s)
Metal Nanoparticles , Nanoparticles , Neoplasms , Zinc Oxide , Animals , Mice , Humans , Nanoparticles/chemistry , Metal Nanoparticles/chemistry , Zinc , Plant Extracts/pharmacology , Plant Extracts/chemistry , Oxides , Neoplasms/drug therapy , Anti-Bacterial Agents/pharmacology , Zinc Oxide/chemistry
5.
Cancers (Basel) ; 14(21)2022 Oct 26.
Article in English | MEDLINE | ID: mdl-36358660

ABSTRACT

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.

6.
J Cell Physiol ; 237(11): 4132-4156, 2022 11.
Article in English | MEDLINE | ID: mdl-36181695

ABSTRACT

Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.


Subject(s)
Cation Transport Proteins , Triple Negative Breast Neoplasms , Humans , Biomarkers, Tumor/therapeutic use , Carrier Proteins , Neoplasm Recurrence, Local , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Zinc/metabolism , Cation Transport Proteins/antagonists & inhibitors
7.
Comb Chem High Throughput Screen ; 25(4): 660-676, 2022.
Article in English | MEDLINE | ID: mdl-33687876

ABSTRACT

AIM: This study aims to develop and establish a computational model that can identify potent molecules for p21-activating kinase 1 (PAK1) Background: PAK1 is a well-established drug target that has been explored for various therapeutic interventions. Control of this protein requires an indispensable inhibitor to curb the structural changes and subsequent activation of signalling effectors responsible for the progression of diseases, such as cancer, inflammatory, viral, and neurological disorders. OBJECTIVE: The study aims to establish a computational model that could identify active molecules which will further provide a platform for developing potential PAK1 inhibitors. METHODS: A congeneric series of 27 compounds were considered for this study, with Ki (nm) covering a minimum of 3 log range. The compounds were developed based on a previously reported Group-I PAK inhibitor, namely G-5555. The 27 compounds were subjected to the SP and XP mode of docking to understand the binding mode, its conformation and interaction patterns. To understand the relevance of biological activity from computational approaches, the compounds were scored against generated water maps to obtain WM/MM ΔG binding energy. Moreover, molecular dynamics analysis was performed for the highly active compound to understand the conformational variability and stability of the complex. We then evaluated the predictable binding pose obtained from the docking studies. RESULTS: From the SP and XP modes of docking, the common interaction pattern with the amino acid residues Arg299 (cation-π), Glu345 (Aromatic hydrogen bond), hinge region Leu347, salt bridges Asp393 and Asp407 was observed, among the congeneric compounds. The interaction pattern was compared with the co-crystal inhibitor FRAX597 of the PAK1 crystal structure (PDB id: 4EQC). The correlation with different docking parameters in the SP and XP modes was insignificant and thereby revealed that the SP and XP's scoring functions could not predict the active compounds. This was due to the limitations in the docking methodology that neglected the receptor flexibility and desolvation parameters. Hence, to recognise the desolvation and explicit solvent effects, as well as to study the Structure-Activity Relationships (SARs) extensively, WaterMap (WM) calculations were performed on the congeneric compounds. Based on displaceable unfavourable hydration sites (HS) and their associated thermodynamic properties, the WM calculations facilitated in understanding the significance of correlation in the folds of activity of highly active (19 and 17), moderately active (16 and 21) and less active (26 and 25) compounds. Furthermore, the scoring function from WaterMap, namely WM/MM, led to a significant R2 value of 0.72 due to a coupled conjunction with MM treatment and displaced unfavourable waters at the binding site. To check the "optimal binding conformation", molecular dynamics simulation was carried out with the highly active compound 19 to explain the binding mode, stability, interactions, solvent-accessible area, etc., which could support the predicted conformation with bioactive conformation. CONCLUSION: This study determined the best scoring function, established SARs and predicted active molecules through a computational model. This will contribute to the development of the most potent PAK1 inhibitors.


Subject(s)
Molecular Dynamics Simulation , Water , Binding Sites , Hydrogen Bonding , Molecular Docking Simulation , Protein Binding , Thermodynamics , Water/chemistry
8.
J Biol Chem ; 298(1): 101406, 2022 01.
Article in English | MEDLINE | ID: mdl-34774800

ABSTRACT

The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel-specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte-macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal-inflammatory-tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel-specific transcriptional regulation of PELP1 in inflammation and possible granulocyte-macrophage colony-stimulating factor-mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies.


Subject(s)
Co-Repressor Proteins , Granulocyte-Macrophage Colony-Stimulating Factor , Neoplasms/metabolism , Trans-Activators , Transcription Factors , Animals , Cell Transformation, Neoplastic , Co-Repressor Proteins/biosynthesis , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Inflammation/genetics , Lipopolysaccharides/pharmacology , Neoplasms/genetics , Neoplasms/pathology , Receptors, Estrogen/metabolism , Trans-Activators/metabolism , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Microenvironment
9.
Biochim Biophys Acta Rev Cancer ; 1877(1): 188668, 2022 01.
Article in English | MEDLINE | ID: mdl-34896436

ABSTRACT

Tamoxifen is a commonly used drug in the treatment of ER + ve breast cancers since 1970. However, development of resistance towards tamoxifen limits its remarkable clinical success. In this review, we have attempted to provide a brief overview of multiple mechanism that may lead to tamoxifen resistance, with a special emphasis on the roles played by the oncogenic kinase- PAK1. Analysing the genomic data sets available in the cBioPortal, we found that PAK1 gene amplification significantly affects the Relapse Free Survival of the ER + ve breast cancer patients. While PAK1 is known to promote tamoxifen resistance by phosphorylating ERα at Ser305, existing literature suggests that PAK1 can fuel up tamoxifen resistance obliquely by phosphorylating other substrates. We have summarised some of the approaches in the mass spectrometry based proteomics, which would enable us to study the tamoxifen resistance specific phosphoproteomic landscape of PAK1. We also propose that elucidating the multiple mechanisms by which PAK1 promotes tamoxifen resistance might help us discover druggable targets and biomarkers.


Subject(s)
Breast Neoplasms , Tamoxifen , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Female , Humans , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , p21-Activated Kinases/genetics
10.
ACS Omega ; 6(41): 26829-26845, 2021 Oct 19.
Article in English | MEDLINE | ID: mdl-34693105

ABSTRACT

p21-Activated kinase 1 (PAK1) is positioned at the nexus of several oncogenic signaling pathways. Currently, there are no approved inhibitors for disabling the transfer of phosphate in the active site directly, as they are limited by lower affinity, and poor kinase selectivity. In this work, a repurposing study utilizing FDA-approved drugs from the DrugBank database was pursued with an initial selection of 27 molecules out of ∼2162 drug molecules, based on their docking energies and molecular interaction patterns. From the molecules that were considered for WaterMap analysis, seven molecules, namely, Mitoxantrone, Labetalol, Acalabrutinib, Sacubitril, Flubendazole, Trazodone, and Niraparib, ascertained the ability to overlap with high-energy hydration sites. Considering many other displaced unfavorable water molecules, only Acalabrutinib, Flubendazole, and Trazodone molecules highlighted their prominence in terms of binding affinity gains through ΔΔG that ranges between 6.44 and 2.59 kcal/mol. Even if Mitoxantrone exhibited the highest docking score and greater interaction strength, it did not comply with the WaterMap and molecular dynamics simulation results. Moreover, detailed MD simulation trajectory analyses suggested that the drug molecules Flubendazole, Niraparib, and Acalabrutinib were highly stable, observed from their RMSD values and consistent interaction pattern with Glu315, Glu345, Leu347, and Asp407 including the hydrophobic interactions maintained in the three replicates. However, the drug molecule Trazodone displayed a loss of crucial interaction with Leu347, which was essential to inhibit the kinase activity of PAK1. The molecular orbital and electrostatic potential analyses elucidated the reactivity and strong complementarity potentials of the drug molecules in the binding pocket of PAK1. Therefore, the CADD-based reposition efforts, reported in this work, helped in the successful identification of new PAK1 inhibitors that requires further investigation by in vitro analysis.

11.
Cell Signal ; 88: 110139, 2021 12.
Article in English | MEDLINE | ID: mdl-34464692

ABSTRACT

Endometriosis is a crippling disease characterized by the presence of endometrium-like tissue or scar outside the uterine cavity, commonly confined to the peritoneal and serosal surfaces of the pelvic organs. 10-15% of women in reproductive age are estimated to be affected by endometriosis. Most of these patients present with infertility and suffer from pelvic pain. The benign disease rarely progresses to malignancy. Regardless of its high prevalence, the pathogenesis of the disease is not fully understood. Treatment options for endometriosis are limited and are often based on a symptomatic approach. The unavailability of proper diagnostic approaches, fewer therapeutic options, and sparse understanding of molecular alterations are responsible for the continued disease burden. Exploring the molecular elements causing the pathogenesis of endometriosis may lead to a number of breakthroughs in the treatment of the illness, such as the discovery of new biomarkers for diagnosis and therapeutic targets that can be a guide to better prognosis and reduced recurrence. The goal of this review is to provide the reader a critical understanding of the disease by summarizing the genetic, immunological, hormonal, and epigenetic deregulations that support the molecular basis for development of endometriotic cyst, with a special focus on the study models needed to analyze these changes in the endometriotic microenvironment.


Subject(s)
Endometriosis , Neoplasms , Biomarkers , Endometriosis/genetics , Endometriosis/pathology , Endometrium/pathology , Female , Humans , Neoplasms/pathology , Tumor Microenvironment
12.
Oncogene ; 40(34): 5327-5341, 2021 08.
Article in English | MEDLINE | ID: mdl-34253860

ABSTRACT

P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncogenic role of RUNX3 in various cancers. Previous findings from our laboratory provided evidence that Threonine 209 phosphorylation of RUNX3 acts as a molecular switch in dictating the tissue-specific dualistic functions of RUNX3 for the first time. Based on these proofs and to explore the translational significance of these findings, we designed a small peptide (RMR) from the protein sequence of RUNX3 flanking the Threonine 209 phosphorylation site. The selection of this specific peptide from multiple possible peptides was based on their binding energies, hydrogen bonding, docking efficiency with the active site of PAK1 and their ability to displace PAK1-RUNX3 interaction in our prediction models. We found that this peptide is stable both in in vitro and in vivo conditions, not toxic to normal cells and inhibits the Threonine 209 phosphorylation in RUNX3 by PAK1. We also tested the efficacy of this peptide to block the RUNX3 Threonine 209 phosphorylation mediated tumorigenic functions in in vitro cell culture models, patient-derived explant (PDE) models and in in vivo tumor xenograft models. These results proved that this peptide has the potential to be developed as an efficient therapeutic molecule for targeting RUNX3 Threonine 209 phosphorylation-dependent tumor phenotypes.


Subject(s)
p21-Activated Kinases , Carcinogenesis , Humans , Oncogenes , Phosphorylation , Protein Serine-Threonine Kinases , Threonine
13.
Biochem J ; 478(12): 2265-2283, 2021 06 25.
Article in English | MEDLINE | ID: mdl-34047336

ABSTRACT

The characteristic features of cancer cells are aberrant (acidic) intracellular pH and elevated levels of phosphatidylserine. The primary focus of cancer research is concentrated on the discovery of biomarkers directed towards early diagnosis and therapy. It has been observed that azoxymethane-treated mice demonstrate an increased expression of calnuc (a multi-domain, Ca2+- and DNA-binding protein) in their colon, suggesting it to be a good biomarker of carcinogenesis. We show that culture supernatants from tumor cells have significantly higher amounts of secreted calnuc compared to non-tumor cells, selectively packaged into exosomes. Exosomal calnuc is causal for epithelial-mesenchymal transition and atypical migration in non-tumor cells, which are key events in tumorigenesis and metastasis. In vitro studies reveal a significant affinity for calnuc towards phosphatidylserine, specifically to its C-terminal region, leading to the formation of 'molten globule' conformation. Similar structural changes are observed at acidic pH (pH 4), which demonstrates the role of the acidic microenvironment in causing the molten globule conformation and membrane interaction. On a precise note, we propose that the molten globule structure of calnuc caused by aberrant conditions in cancer cells to be the causative mechanism underlying its exosome-mediated secretion, thereby driving metastasis.


Subject(s)
Carcinoma, Squamous Cell/secondary , Exosomes/metabolism , Mouth Neoplasms/pathology , Nucleobindins/metabolism , Pancreatic Neoplasms/pathology , Phosphatidylserines/metabolism , Tumor Microenvironment , Animals , Carcinoma, Squamous Cell/metabolism , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Humans , Mice , Mice, Inbred C57BL , Mouth Neoplasms/metabolism , Nucleobindins/genetics , Pancreatic Neoplasms/metabolism , Tumor Cells, Cultured
14.
Exp Cell Res ; 403(2): 112613, 2021 06 15.
Article in English | MEDLINE | ID: mdl-33901448

ABSTRACT

The Hippo signaling pathway is a tumor suppressor pathway that plays an important role in tissue homeostasis and organ size control. KIBRA is one of the many upstream regulators of the Hippo pathway. It functions as a tumor suppressor by positively regulating the core Hippo kinase cascade. However, there are accumulating shreds of evidence showing that KIBRA has an oncogenic function, which we speculate may arise from its functions away from the Hippo pathway. In this review, we have attempted to provide an overview of the Hippo signaling with a special emphasis on evidence showing the paradoxical role of KIBRA in cancer.


Subject(s)
Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Signal Transduction/genetics , Adherens Junctions/metabolism , Adherens Junctions/ultrastructure , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Focal Adhesions/metabolism , Focal Adhesions/ultrastructure , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/metabolism , Hippo Signaling Pathway , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Serine-Threonine Kinase 3 , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
15.
Sci Rep ; 11(1): 1478, 2021 01 14.
Article in English | MEDLINE | ID: mdl-33446714

ABSTRACT

Camptothecin the third most in demand alkaloid, is commercially extracted in India from the endangered plant, Nothapodytes nimmoniana. Endophytes, the microorganisms that reside within plants, are reported to have the ability to produce host-plant associated metabolites. Hence, our research aims to establish a sustainable and high camptothecin yielding endophyte, as an alternative source for commercial production of camptothecin. A total of 132 endophytic fungal strains were isolated from different plant parts (leaf, petiole, stem and bark) of N. nimmoniana, out of which 94 were found to produce camptothecin in suspension culture. Alternaria alstroemeriae (NCIM1408) and Alternaria burnsii (NCIM1409) demonstrated camptothecin yields up to 426.7 ± 33.6 µg/g DW and 403.3 ± 41.6 µg/g DW, respectively, the highest reported production to date. Unlike the reported product yield attenuation in endophytes with subculture in axenic state, Alternaria burnsii NCIM1409 could retain and sustain the production of camptothecin up to ~ 200 µg/g even after 12 continuous subculture cycles. The camptothecin biosynthesis in Alternaria burnsii NCIM1409 was confirmed using 13C carbon labelling (and cytotoxicity analysis on different cancer cell lines) and this strain can now be used to develop a sustainable bioprocess for in vitro production of camptothecin as an alternative to plant extraction.


Subject(s)
Alternaria/metabolism , Camptothecin/biosynthesis , Camptothecin/isolation & purification , Alkaloids/metabolism , Camptothecin/metabolism , Endophytes/metabolism , India , Magnoliopsida/metabolism , Plant Leaves/metabolism
16.
J Mol Neurosci ; 71(4): 724-733, 2021 Apr.
Article in English | MEDLINE | ID: mdl-32964396

ABSTRACT

Malignant astrocytomas presenting in humans of any age group are a challenge to diagnose and treat. Hence, there is a quest for new markers to ascertain their grades and predict disease outcomes. Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a nuclear receptor co-regulator, is an oncogene found in various cancers. We postulate that by screening for PELP1, its correlation with survival outcomes of patients across various grades can indicate a plausible novel diagnostic marker and a potential therapeutic target in gliomas. Immunostaining of 100 cases of astrocytomas for PELP1 was performed on paraffin-embedded sections. Results showed that PELP1 expression increases with higher grades; the mean H-score of PELP1 in grade-I astrocytomas was determined to be 112.3, whereas in grade-IV it was 235.1 (P value = 0.0001). Survival analysis of patients with H-score of 200-300 was only 8.8% and 68.8% in patients with scores of 0-100. PELP1 expression in high-grade astrocytomas is an important factor in determining the outcomes. Graphical abstract Evaluation of molecular expression of PELP1 along with Ki-67 LI signifies a linear increase in its expression pattern among different grades of astrocytomas from low- to high-grade tumors, which can serve as a potential prognostic molecular marker in differentiating various types of astrocytomas in humans.


Subject(s)
Astrocytoma/metabolism , Brain Neoplasms/metabolism , Co-Repressor Proteins/metabolism , Glutamic Acid/metabolism , Ki-67 Antigen/metabolism , Proline/metabolism , Transcription Factors/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Astrocytoma/pathology , Brain Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasm Grading
17.
Cancer Invest ; 39(1): 98-113, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33251876

ABSTRACT

Glioblastomas are the primary malignant tumors of brain tissues with poor prognosis and highly invasive phenotypes. Till now Ki-67 LI has emerged as a well-studied proliferation marker that aids in tumor grading, but labeling index alone cannot predict overall survival in gliomas. P21 activated kinase 1 (PAK1) - a serine/threonine kinase has been shown to function as downstream nodule for various oncogenic signaling pathways that promote neoplastic changes. This study is designed to evaluate the expression of PAK1 across various grades and its correlation with Ki-67 LI and overall survival rates among a total number of 140 clinical brain tumors of glioma patients. We also studied the activation status of phospho PAK1 in glioma tissues and established the role of PAK1 in proliferation of glioblatoma cell lines under γ-irradiation.This study provides molecular evidence signifying the role of PAK1 and its activation status in the progression of Gliomas to more aggressive phenotypes.


Subject(s)
Brain Neoplasms/enzymology , Glioma/enzymology , p21-Activated Kinases/metabolism , Adult , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/physiology , Female , Glioma/genetics , Glioma/pathology , Humans , Male , Middle Aged , Young Adult
18.
Gene ; 760: 144991, 2020 Nov 15.
Article in English | MEDLINE | ID: mdl-32717309

ABSTRACT

Breast cancer is the most frequently diagnosed cancer in women worldwide. Identifying reliable biomarkers and druggable molecular targets pose to be a significant quest in breast cancer research. p21-activated kinase 1 (PAK1) is a serine/threonine kinase that direct cell motility, cytoskeletal remodelling, and has been shown to function as a downstream regulator for various cancer signalling cascades that promote cell proliferation, apoptosis deregulation and hasten mitotic abnormalities, resulting in tumor formation and progression. The heterogeneity and acquired drug resistance are important factors that challenge the treatment of breast cancer. p21-activated kinase 1 signalling is crucial for activation of the Ras/RAF/MEK/ERK, PI3K/Akt/mTOR and Wnt signalling cascades which regulate cell survival, cell cycle progression, differentiation, and proliferation. A study involving proteogenomics analysis on breast cancer tissues showed the PAK1 as outlier kinase. In addition to this, few outlier molecules were identified specific to subtypes of breast cancer. A few substrates of PAK1 in breast cancer are already known. In this paper, we have discussed a similar approach called Kinase Interacting Substrate Screening (KISS) for the identification of novel oncogenic substrates of p21-activated kinase specific to subtypes of breast cancer. Such high throughput approaches are expected to accelerate the process of identifying novel drug targets and biomarkers.


Subject(s)
Breast Neoplasms/metabolism , p21-Activated Kinases/metabolism , Animals , Apoptosis/drug effects , Apoptosis/physiology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cell Survival/drug effects , Cell Survival/physiology , Female , Humans , Signal Transduction , p21-Activated Kinases/genetics
19.
J Nanobiotechnology ; 18(1): 74, 2020 May 14.
Article in English | MEDLINE | ID: mdl-32410712

ABSTRACT

BACKGROUND: Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, known to possess anti-oxidant, anti-cancer and anti-viral activities and is being used in traditional medicine. However, toxicity studies indicated liver and kidney damage despite its immense medicinal properties. There has been a recent increase of curiosity in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA and for targeted delivery to the site of tissue by chemical derivatives. In this regard, an analog of NDGA, Acetyl NDGA (Ac-NDGA), has been synthesized based on a previous procedure and formulated as a nanostructured complex with Polycaprolactone/Polyethylene glycol polymer matrices, by o/w solvent evaporation method. RESULTS: The drug-incorporated polymeric nanospheres exhibited a drug load of 10.0 ± 0.5 µg drug per mg of nanospheres in acetonitrile solvent with 49.95 ± 10% encapsulation efficiency and 33-41% drug loading capacity with different batches of nanospheres preparation. The in vitro drug release characteristics indicated 82 ± 0.25% drug release at 6 h in methanol. Further, the nanospheres have been characterized extensively to evaluate their suitability for therapeutic delivery. CONCLUSIONS: The present studies indicate a new and efficient formulation of the nanostructured AcNDGA with good therapeutic potential.


Subject(s)
Antioxidants , Masoprocol , Nanostructures/chemistry , Polymers/chemistry , Antioxidants/chemistry , Antioxidants/pharmacokinetics , Antioxidants/pharmacology , Cell Survival/drug effects , Hep G2 Cells , Humans , Masoprocol/chemistry , Masoprocol/pharmacokinetics , Masoprocol/pharmacology , Materials Testing , Particle Size
20.
Curr Cancer Drug Targets ; 20(2): 86-103, 2020.
Article in English | MEDLINE | ID: mdl-31642411

ABSTRACT

Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used in traditional medicine in North America and Mexico. However, its prolonged consumption leads to liver damage and kidney dysfunction. Despite its toxicity and side effects, there is little awareness to forbid its consumption and its use in the treatment of medical ailments has continued over the years. Several reports discuss its therapeutic efficiency and its medical applications have tremendously been on the rise to date. There has been a recent surge of interest in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA. Although several NDGA derivatives have been chemically synthesized as evidenced by recent literature, there is a paucity of information on their therapeutic efficacies. This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications. We suggest that NDGA derivatives should be investigated more in terms of chemical synthesis with preferred conformational structures and exploit their biological potentials with future insights to explore in this direction to design and develop structurally modified NDGA derivatives for potential pharmacological properties.


Subject(s)
Masoprocol/pharmacology , Animals , Humans , Hydrophobic and Hydrophilic Interactions , Masoprocol/chemical synthesis , Masoprocol/therapeutic use , Masoprocol/toxicity , Molecular Conformation
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