Cancer Therapeutics Research Articles

Role of transcription factors in metastasis of breast cancer

Metastasis causes a majority of deaths in breast cancer patients. Metastasis is the spread of cancer to distant sites in the body away from the primary tumor, creating secondary tumors, or metastases. A tumor metastasizes when cancer cells strategically regulate genes that play a role in angiogenesis, epithelial-mesenchymal transition (EMT), migration, invasion, and regulation of the cell cycle to bypass apoptosis and increase proliferation and stemness. Several transcription factors have also been identified to play a role in metastatic breast cancer, as they enable invasion, intravasation, transport, extravasation, and colonization of metastasis through other processes such as angiogenesis and EMT, making them a prime target for cancer treatment. Understanding how transcription factors play a role in breast cancer metastasis will enable the development of targeted therapeutics for breast cancer. This paper reviews the roles of E2Fs, hypoxia-inducible factors (HIFs), EMT master regulators, sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX), E26 transformation-specific (ETS), Yin Yang 1 (YY1), forkhead box M1 (FoxM1), BTB domain and CNC homology 1 (Bach1), sineoculis homeobox homolog (SIX), runt-related transcription factor 2 (RUNX2), myelocytomatosis (MYC), Kruppel-like factors (KLFs), and c-Jun in breast cancer metastasis.

Natural killer cells as promising candidates in Cancer therapeutics and related immune resistance in tumor microenvironment

Natural killer (NK) cells, as critical components of the innate immune system, have emerged as promising candidates in cancer therapy due to their ability to recognize and destroy tumor cells without prior sensitization. Their mechanisms of action, including perforin-granzyme release and antibody-dependent cellular cytotoxicity (ADCC), position them as versatile agents in cancer immunotherapy. Recent advancements, such as chimeric antigen receptor (CAR)-NK cells and cytokine-based stimulation, have demonstrated enhanced efficacy and reduced side effects compared to conventional immunotherapies. However, the immunosuppressive tumor microenvironment (TME) remains a significant obstacle, imposing challenges like immune checkpoint activation, cytokine suppression, and metabolic constraints that impair NK cell activity. This paper explores the therapeutic potential of NK cells, the challenges of immune resistance in the TME, and emerging strategies to enhance NK cell efficacy. Addressing these challenges is crucial for optimizing NK cell-based treatments and achieving durable responses in cancer patients.

Beginning at the ends: telomere and telomere-based cancer therapeutics.

Telomeres, which are situated at the terminal ends of chromosomes, undergo a reduction in length with each cellular division, ultimately reaching a critical threshold that triggers cellular senescence. Cancer cells circumvent this senescence by utilizing telomere maintenance mechanisms (TMMs) that grant them a form of immortality. These mechanisms can be categorized into two primary processes: the reactivation of telomerase reverse transcriptase and the alternative lengthening of telomeres (ALT) pathway, which is dependent on homologous recombination (HR). Various strategies have been developed to inhibit telomerase activation in 85-95% of cancers, including the use of antisense oligonucleotides such as small interfering RNAs and endogenous microRNAs, agents that simulate telomere uncapping, expression modulators, immunotherapeutic vaccines targeting telomerase, reverse transcriptase inhibitors, stabilization of G-quadruplex structures, and gene therapy approaches. Conversely, in the remaining 5-15% of human cancers that rely on ALT, mechanisms involve modifications in the chromatin environment surrounding telomeres, upregulation of TERRA long non-coding RNA, enhanced activation of the ataxia telangiectasia and Rad-3-related protein kinase signaling pathway, increased interactions with nuclear receptors, telomere repositioning driven by HR, and recombination events between non-sister chromatids, all of which present potential targets for therapeutic intervention. Additionally, combinatorial therapy has emerged as a strategy that employs selective agents to simultaneously target both telomerase and ALT, aiming for optimal clinical outcomes. Given the critical role of anti-TMM strategies in cancer treatment, this review provides an overview of the latest insights into the structure and function of telomeres, their involvement in tumorigenesis, and the advancements in TMM-based cancer therapies.

Advances towards potential cancer therapeutics targeting Hippo signaling.

Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.

Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18

BackgroundInterleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8+ T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part...

Bridging the gap between tumor and disease: Innovating cancer and glioma models.

Recent advances in cancer biology and therapeutics have underscored the importance of preclinical models in understanding and treating cancer. Nevertheless, current models often fail to capture the complexity and patient-specific nature of human tumors, particularly gliomas. This review examines the strengths and weaknesses of such models, highlighting the need for a new generation of models. Emphasizing the critical role of the tumor microenvironment, tumor, and patient heterogeneity, we propose integrating our advanced understanding of glioma biology with innovative bioengineering and AI technologies to create more clinically relevant, patient-specific models. These innovations are essential for improving therapeutic development and patient outcomes.

Construction and Isolation of Recombinant Vaccinia Virus by Homologous Recombination Using Fluorescent Protein Markers.

Genetic modification of vaccinia virus (VACV) is a fundamental and valuable research technique in elucidating the function of VACV genes, as well as the development as vaccine vectors for other infectious diseases, oncolytic therapeutics for cancers, and protein expression systems in mammalian cells. Because of the large size of poxvirus genome and noninfectious feature of the naked viral DNA, construction of recombinant VACV relies on intracellular homologous recombination between transfected DNA and replicating viral DNA in infected cells occurred in VACV infected cells. The efficiency of homologous recombination event for vaccinia virus is relatively low, and recombinant viruses only account for 0.1% of progeny viruses. Therefore, fluorescent protein markers are often included in the transfected DNA to facilitate the selection and screening of recombined viruses. Here we provide a detailed procedure for the design, generation, isolation, and detection of recombinant VACV by homologous recombination using fluorescent protein markers.

Rapid Generation of Recombinant Poxviruses Using CRISPR/Cas9 Gene Editing.

The low-frequency natural recombination that is detected in poxvirus-infected cells has long been used to genetically modify poxviruses. Such recombinant poxviruses have found many applications as vaccines for preventing infectious diseases and as experimental cancer therapeutics. Unfortunately, these methods are time consuming, can leave behind "scars" or selectable markers, and many months of work may be required to generate plaque-purified recombinants bearing multiple virus gene substitutions, deletions, and/or inserted transgenes. Over the last decade, several reports have described how CRISPR/Cas9 technologies can be used to better facilitate genetic manipulation of vaccinia virus (VACV). These protocols use Cas9/gRNA complexes to introduce double-stranded breaks into specific sites in virus genomic DNA either in vivo or in vitro. Recombination-repair reactions are then employed to repair the breaks using transfected DNAs encoding the required homologies and desired mutation(s). Here we describe a method where we combine CRISPR/Cas9 genome editing in vitro, followed by Leporipoxvirus-catalyzed repair and reactivation of the cut VACV DNA using repair fragments provided in trans. This method optimizes several steps in the preparation of the CRISPR/Cas9-cut VACV DNA and can be used to introduce mutations at multiple sites without requiring selectable markers. It also provides some guidance regarding how the position of the CRISPR/Cas9-cuts can affect co-conversion of flanking markers embedded in the repair fragment. The method allows researchers to quickly generate recombinant VACV bearing multiple genetic alterations and using only a single round of reactivation and plating.

Efficacy Assessment of Sulfated Flavanol Functionalized Silver Nanoparticles against MCF-7 Breast Cancer

Aim: The present research work aims to formulate a cost-effective and less toxic drug for specific and selective delivery at the tumor site. Background: Existing therapeutics, such as chemo, surgery, etc., for fast-paced MCF-7 breast cancer, still face challenges, especially due to their toxic side effects. The unique properties of metal nanoparticles embedded in anti-oxidant plant polymers have sparked great interest in the formulation of less toxic-targeted drugs for cancer cure. Objective: The present work aims to synthesize a targeted formulation of colloidal nanosilver by surface engineering of silver nanoparticles using plant polymers in electrolytic deposition technique, developed indigenously at the institute lab. Methods: A current is passed through an elctrolyte, AgNO3, which splits it into ions. The positive ions of Ag deposit over LDPE wrapped carbon cathode and negative ion, NO3, is liberated. Ag+ ions get capped in-situ. These surface-modified silver nanoparticles formulate a colloidal solution. UV-visible and FTIR spectroscopy, TEM-EDX, and XRD were used to validate asprepared formulation and in vivo human tumor xenograft model in NOD-SCID mouse for efficacy against MCF-7 breast cancer. Results: The as-synthesized formulation consists of pure spherical poly-dispersed silver nanoparticles of average size 5.4 nm, coated with sulphated flavanols. The efficacy evaluation reported that it significantly, T/C = 0.53, reduced tumor volumes with a 100% survival rate and change in animal body weight <4 gms. Conclusion: The as-synthesized formulation can be used as a potential neo-adjuvant or adjuvant drug along with existing therapeutics for MCF-7 breast cancer, significantly reducing the toxicity and cost.

Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology.

Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.

Insight in Quinazoline-based HDAC Inhibitors as Anti-cancer Agents.

Cancer remains a primary cause of death globally, and effective treatments are still limited. While chemotherapy has notably enhanced survival rates, it brings about numerous side effects. Consequently, the ongoing challenge persists in developing potent anti-cancer agents with minimal toxicity. The versatile nature of the quinazoline moiety has positioned it as a pivotal component in the development of various antitumor agents, showcasing its promising role in innovative cancer therapeutics. This concise review aims to reveal the potential of quinazolines in creating anticancer medications that target histone deacetylases (HDACs).

Engineered immune cell-based therapeutics for female reproductive tract cancers: Advances and future prospects

Engineered immune cell-based therapeutics for female reproductive tract cancers: Advances and future prospects

Cryptotanshinone Suppresses the STAT3/BCL-2 Pathway to Provoke Human Bladder Urothelial Carcinoma Cell Death.

Bladder cancer is one of the most common human malignancies worldwide. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is crucial to driving malignant progression and predicting poor prognosis of multiple human cancers, including bladder cancer, making STAT3 a promising target of cancer therapeutics. Cryptotanshinone (CTS) is an anticancer ingredient of Danshen (Salvia miltiorrhiza), a top-graded Chinese medicinal herb. However, whether CTS targets STAT3 to exert its cytotoxic effect on human bladder cancer remains unknown. Herein, we demonstrated that CTS is cytotoxic to multiple human urinary bladder transitional cell carcinoma (TCC) cell lines while sparing normal human urothelial cells. CTS provoked apoptosis-dependent bladder TCC cytotoxicity, as apoptosis blockage by z-VAD-fmk markedly rescued the clonogenicity of CTS-treated cells. Besides, CTS was found to suppress constitutive and interleukin 6-inducible activation of STAT3, evidenced by the downregulation of STAT3 tyrosine 705 phosphorylation and BCL2, a recognized STAT3 transcriptional target. Notably, ectopic expression of a dominant-active STAT3 mutant (STAT3-C) or BCL-2 alleviated CTS-induced apoptosis and clonogenicity inhibition, thus confirming STAT3 blockade as a pivotal mechanism of CTS's cytotoxic action on bladder TCC cells. Lastly, immunoblotting revealed that CTS lowered the levels of active JAK2, an upstream kinase that mediates STAT3 tyrosine 705 phosphorylation. Altogether, we conclude that the blockade of the JAK2/STAT3/BCL-2 antiapoptotic signaling axis is a vital mechanism whereby CTS provokes bladder cancer cytotoxicity. The current evidence implicates CTS's potential to be translated into a bladder cancer therapeutic agent.

Anti‑angiogenic effect of Bryopsis plumosa‑derived peptide via aquaporin 3 in non‑small cell lung cancer.

Developing novel anti‑angiogenic agents with minimal toxicity is notably challenging for cancer therapeutics. The discovery and development of peptides, whether derived from natural sources or synthesized, has potential for developing anti‑angiogenic agents characterized by their ability to penetrate cancer cells, high specificity and low toxicity. The present study identified a Bryopsis plumose‑derived anticancer and anti‑angiogenesis marine‑derived peptide 06 (MP06). A 22‑amino acid peptide was synthesized and conjugated with fluorescein isothiocyanate (FITC‑MP06) for intracellular localization in H1299 non‑small cell lung cancer cells. Regulatory effects of this peptide on the viability, migration and self‑renewal of lung cancer cells was assessed. Furthermore, anti‑angiogenic effect of MP06 was investigated by monitoring vascular tube formation in human umbilical vein endothelial cells and a zebrafish model. Aquaporin (AQP)3, a membrane channel in various tissues, is involved in regulating stemness, epithelial‑mesenchymal transition (EMT) and angiogenesis. MP06 downregulated AQP3 expression. Consistently, AQP3 knockdown by RNA silencing downregulated its gene expression, leading to a decrease in stemness, EMT and angiogenesis properties in H1299 cells. MP06 could thus serve as a novel therapeutic target with anticancer and angiogenesis properties for non‑small cell lung cancer.

In medicine today – Cancer and the prorogation of clinical reality in favour of probabilistic outcomes

Abstract How essential is the randomised trial in cancer therapeutics? Is it conceivable that prospective randomised clinical trials in cancer medicine could, one day, safely be abandoned in favour of Phase II studies supplemented with real-world data from cancer centres, without detriment to the progress of cancer therapeutics or the welfare of cancer sufferers? If feasible, such practice could reduce the cost of new drug development, while freeing clinical investigators from the ethical burden of random allocation of treatment or indeed providing no therapy with the administration of a placebo to cancer sufferers.

Nanoparticle-Assisted Cancer Imaging and Targeted Drug Delivery for Early-Stage Tumor Detection and Combined Diagnosis-Therapy Systems for Improved Cancer Management

Nanoparticle-assisted imaging and targeted drug delivery represent a transformative approach in cancer diagnostics and therapeutics, particularly for early-stage tumor detection and integrated diagnosis- therapy systems. This review explores recent advancements in nanoparticle technology for magnetic resonance imaging (MRI), computed tomography (CT), optical imaging, and ultrasound, emphasizing the efficacy of nanoparticles such as superparamagnetic iron oxide nanoparticles (SPIONs), gold and bismuth nanoparticles, and quantum dots as contrast agents. Nanoparticles offer unique advantages, including enhanced permeability and retention (EPR) effects, ligand-receptor targeting, and microenvironment-responsive drug release, which improve localization and accumulation in tumor tissues. Additionally, dual-function theranostic systems utilizing nanoparticles enable simultaneous diagnostic imaging and therapy, allowing real-time monitoring of therapeutic efficacy and minimizing off-target effects. The integration of nanoparticles for both diagnostic and therapeutic purposes holds significant promise for precision oncology, providing a more personalized, minimally invasive, and effective cancer management strategy. This review also discusses current limitations, including issues of biocompatibility, toxicity, and regulatory challenges, while proposing future directions to overcome these barriers. By presenting a comprehensive analysis of nanoparticle platforms in oncology, this paper aims to underscore their potential in revolutionizing cancer diagnosis and therapy, ultimately contributing to improved patient outcomes and advancing the field of nanomedicine.

Recent advances in nanomedicine for innovative oral cancer therapeutics—a review

Recent advances in nanomedicine for innovative oral cancer therapeutics—a review

Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

KIF18A inhibition: the next big player in the search for cancer therapeutics.

Kinesin-like protein 18A (KIF18A) is a member of the kinesin family of molecular motor proteins, which utilise energy from the hydrolysis of adenosine triphosphate (ATP) to regulate critical cellular processes such as chromosome movement and microtubule dynamics. KIF18A plays a vital role in controlling microtubule length, which is crucial for maintaining proper cell function and division. Notably, increased expression levels of KIF18A have been observed in various types of cancer, indicating its potential involvement in tumour progression. Although preclinical studies have demonstrated that KIF18A is not essential for normal somatic cell division, it appears to be crucial for the survival and division of cancer cells, particularly those exhibiting chromosomal instability. This dependency makes KIF18A a promising target for developing new therapeutic strategies aimed at treating chromosomally unstable cancers. This review delves into the structural and functional aspects of KIF18A, and its role in cancer development, and evaluates current and emerging approaches to targeting KIF18A with innovative cancer treatments.

Unveiling novel type 1 inhibitors for targeting LIM kinase 2 (LIMK2) for cancer therapeutics: An integrative pharmacoinformatics approach

LIMK2 is crucial in regulating actin cytoskeleton dynamics, significantly contributing to cancer cell proliferation, invasion, and metastasis. Inhibitors like LIMKi3 effectively suppress LIMK2 kinase activity by directly affecting actin polymerization and preventing the formation of structures like filopodia and lamellipodia, which are typical of motile cancer cells. By modulating these actin dynamics, LIMKi3 inhibits cancer cell migration and invasion, reducing the potential for metastasis. Thus, this study aims to explore potential anti-cancer therapeutic LIMK2 inhibitors with properties resembling LIMKi3. Henceforth, molecular docking was utilized in this study to comprehend the ATP mimetic binding mode of LIMKi3, followed by Pharmacophore-based virtual screening to identify small molecules resembling LIMKi3. In addition, molecular dynamics simulations were performed to explore the dynamic behavior of LIMK2 and potential inhibitors. Further, network analysis and binding free energy calculations were implemented to comprehensively assess the interactions between the compounds and LIMK2. In molecular docking, LIMKi3 demonstrated an ATP mimetic hinge binding mode with hydrogen bonds at Ile408. Among the screened compounds (NCI300395, ChemDiv-8020–2508, and ChemDiv-7997–0024), three displayed "ADRH" pharmacophoric features like LIMKi3, with favorable ADMET properties, higher binding affinity, and significant hydrogen bond interactions at Ile408. LIMK2-inhibitor complexes showed lower RMSD than LIMK2-LIMKi3, indicating higher equilibrium by identified compounds. Protein-drug Complexes exhibited significant inter-domain correlation in N-lobe residues of LIMK2, including conserved β3, αC, and Hinge residues. Binding free energy analysis ranked LIMK2-NCI300395 highest, followed by LIMK2-ChemDiv-7997–0024 and LIMK2-ChemDiv-8020–2508, highlighting their potential as effective LIMK2-targeting compounds. Hence, this study emphasizes LIMKi3's significance and identifies potential candidates (NCI300395, ChemDiv-7997–0024, and ChemDiv-8020–2508) for developing cancer therapeutics targeting LIMK2. These findings open avenues for further investigations into the complex interplay between cytoskeletal dynamics and cancer progression.