It is predicted that over 29 million individuals will receive a cancer diagnosis in 2040, making cancer one of the major causes of death globally. One of the biggest obstacles to being overcome in the treatment of cancer is drug resistance, which is mostly to blame for this high death rate. Research has therefore concentrated on developing new therapeutic tools, particularly those that enable individualized care based on the features of the patient. Although ensuring the quality of life for cancer patients has been a concern for the scientific community, attempts have been made to find alternatives to the creation of new pharmaceuticals since researchers are aware of the rising expenses associated with cancer therapy. The trend towards drug repurposing is growing as a strategy to accelerate drug development, utilizing the proven safety and effectiveness of existing approved drugs. The central theme of this review centered on exploring potential repurposed medications for treating cancer. The central theme of this review revolves around Adapalene, traditionally known for its acne treatment benefits, now being evaluated for its potential in cancer therapy. The latest details of Adapalene, a repurposed cancer therapeutic candidate, its therapeutic potential, Pharmacokinetic Profile, and the molecular interactions behind its anti-tumor efficacy are also included in this paper. In addition, medication combinations have also been covered here as a useful tactic to get around the restrictions associated with drug repurposing. The review concludes that drug repurposing represents one of the most promising approaches in cancer treatment and incorporating combination therapy can address challenges encountered in this field. Regarding drug repurposing, Adapalene has demonstrated significant efficacy in treating various types of cancer, including skin cancer, colon cancer, and breast cancer.

Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1.

Chloroquine (CQ) an autophagy antagonist has been recently explored as a repurposable medicine for cancer; however the underlying mechanisms are still unclear. Here in this study we investigated the effect of CQ on colorectal cancer cells with an aim to elucidate the molecular mechanism involved. We report for the first time that CQ suppresses hypoxia-induced cell growth and survival of HCT-116 cells due to the reduction in glycolytic capacity and NAD+ production subsequent to the inhibition of PDK1 by CQ. Furthermore, in silico and in vitro studies show that CQ induces structural alteration in the PDK1 protein, leading to its destabilisation, thus favouring its enhanced protease mediated degradation which is inhibited by MG-132 protease inhibitor. In addition to this, suppression of PDK1 by CQ results in mitochondrial damage through excessive production of ROS as reflected by the reduction in MMP, with subsequent induction of apoptosis by promoting PARP cleavage and caspase activation. These findings advocate CQ as a potent repurposable chemotherapeutic medication against colorectal cancer and as a novel inhibitor of PDK1.

B-cell lymphoma/leukemia gene-2 (Bcl-2) is the primary proto-oncogene that has been shown to work by preventing apoptosis/programmed cell death. Bcl-2 combines a variety of cell-generated signals associated to the survival and death of cells. In glioma, lung, and breast cancer, Bcl-2 over-expression has been linked to an increase in invasion and migration. Many treatment regimens that target Bcl2 have been established and approved, and thus increasing the survival rates of the patients. The primary goal of this research was to recognize new therapeutic compounds that target Bcl2 and assess Bcl2 expression pattern in BC patients. We used various bioinformatic tools as well as several in vitro assays to look out the expression and inhibition of Bcl2 in BC. Our study depicted that Bcl2 had a strong connection with tumour stroma, notably with suppressor cells originating from myeloid tissues. Moreover, in vitro and in silico research identified Paclitaxel as a promising natural substance that targets Bcl2. Overall, this work shows that Bcl2 overexpression accelerates the development of BC, and that targeting Bcl2 in combination with other drugs will dramatically improve BC patient’s response to treatment and prevent the emergence of drug resistance.

Aim Doxorubicin (DOX) is one of the most commonly used chemotherapeutic medications for treating several malignancies, including TNBC. However, severe toxicity and the development of resistance to drugs, limits its therapeutic index. As a result, there is a crucial need for the advancement of novel medications that boost the efficacy of Doxorubicin while decreasing its toxicity. Studies have shown that the Z. zerumbet-isolated sesquiterpene zerumbone (ZER) is a potent anti-proliferative molecule against several cancers including BC. This study intended to assess the antitumor activity of ZER in TNBC cells in combination with Doxorubicin. Methods MTT and Chou-Talay techniques were used to evaluate cell viability and pharmacodynamic interactions. Western blotting. flow cytometry, and fluorescence microscopy were used to assess the molecular mechanism underlying the anti-tumor activity of DOX-ZER combination. Results DOX and ZER combination significantly reduced the cell viability and showed synergistic impact on migration, proliferation, and colony formation potential of TNBC cells. Moreover, DOX-ZER combination resulted in enhanced ROS accumulation, activating MAPK3 mediated apoptosis and cell cycle arrest. Conclusions Our findings show that ZER is a potent anticancer molecule that may be used in combination with DOX to enhance therapeutic efficacy and reduce the development of therapeutic resistance.

Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase has emerged as a critical target in chemotherapy. 5-Fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells. One-pot organic synthesis processes using a single solvent were used for the synthesis of drug analogues of Uracil. Integrated bioinformatics using GEPIA2, UALCAN, and KM plotter were utilized to study the expression pattern and prognostic significance of TYMS, the key target gene of 5-fluorouracil in breast cancer patients. Cell viability, cell proliferation, and colony formation assays were used as in vitro methods to validate the in silico lead obtained. BC patients showed high levels of thymidylate synthase, and high expression of thymidylate synthase was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for thymidylate synthase. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase.

Abstract Breast cancer (BC) is a significant cause of mortality associated with cancer, presenting a substantial risk to women's health and overall welfare on a global scale. Despite notable progress in BC treatment, the prognosis for metastatic BC remains unfavorable, ultimately leading to fatality. To develop advanced therapeutic approaches, it is imperative to have a comprehensive comprehension of the underlying process responsible for the systemic dispersion of cancer cells. Numerous experimental findings indicate that an epithelial-to-mesenchymal transition (EMT) is essential in the intricate progression of metastasis formation. EMT is a crucial initial stage observed in certain highly aggressive malignancies, such as breast cancer, facilitating the processes of invasion and metastasis. The current study assessed the impact of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1) on breast cell lines, specifically MDA-MB-468, MDA-MB-231, and MCF10A. The experimental techniques employed in this study were qPCR, western blotting, and subsequent investigation of gene-gene interactions. Cell migration and proliferation assays were also conducted to investigate the following impacts of EGF and IGF-1 on breast cells. A study revealed that IGF-1 can augment EMT induced by EGF. Furthermore, it was observed that the expression levels of EMT-inducing transcription factors, namely snail, slug, zeb1, and zeb2, were increased in breast cells that were treated with EGF or IGF-1. Furthermore, it was observed that the stimulation of cell proliferation in metastatic BC cell lines is significantly enhanced upon administration of EGF and IGF-1. Notably, the observed augmentation in cellular proliferation was not discernible in non-malignant breast cells. Additionally, it was revealed that the morphology of BC cell lines undergoes alterations upon exposure to EGF and IGF-1. In contrast, it has been observed that the shape of normal BC stays unaltered, suggesting that the stimulation of EMT in breast tumor cells is induced explicitly by growth factors such as EGF and IGF-1. These research findings indicate that incorporating EGFR/IGF-R signaling as a potential therapeutic target, in conjunction with conventional treatment methods, exhibits substantial potential in attenuating tumor growth and progression, prolonging the overall survival rates of cancer patients.

Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the way for developing effective therapeutic modalities for effective treatment of TNBC.

Chemotherapy is the only therapeutic option due to the lack of hormone receptors on breast carcinoma cells. The nanomedical researcher and oncologist were inspired to create unique and effective nanotherapies to handle such a large TNBC issue because of cancer's tendency to spread and recurrence, as well as its low survival and prognosis. Nanocarriers have recently become the focus for improved availability, tailored cellular absorption, and minimum cytotoxicity. Such smart nanovehicles are equipped with all of the required armaments (drugs, tracking probes, and ligands) and are intended to target specific TNBC cells on site. Nanosoldiers have extraordinary ability to eliminate TNBC cells due to their variety in terms of drug loading, material composition, and releasing process, capability to adjust in vivo drug distribution, multifunctional properties facilitating the identification, therapy, and monitoring, and so on. This chapter aims to provide a fundamental overview of the novel nanotherapeutic methods used in the management and therapy of TNBC.

BACKGROUND:DNA Topoisomerase II Alpha (TOP2A), a protein-coding gene, is central to the replication process and has been found deregulated in several malignancies, including breast cancer. Several therapeutic regimens have been developed and approved for targeting TOP2A and have prolonged the survival of cancer patients. However, due to the inherent nature of the tumor cell to evolve, the earlier positive response turns into a refractory chemoresistance in breast cancer patients.OBJECTIVE:The study's main objective was to analyze the expression pattern and prognostic significance of TOP2A in breast cancer patients and screen new therapeutic molecules targeting TOP2A.METHODS:We utilized an integrated bioinformatic approach to analyze the expression pattern, genetic alteration, immune association, and prognostic significance of TOP2A in breast cancer (BC) and screened natural compounds targeting TOP2A, and performed an in silico and an in vitro analysis.RESULTS:Our study showed that TOP2A is highly overexpressed in breast cancer tissues and overexpression of TOP2A correlates with worse overall survival (OS) and relapse-free survival (RFS). Moreover, TOP2A showed a high association with tumor stroma, particularly with myeloid-derived suppressor cells. Also, in silico and in vitro analysis revealed cryptolepine as a promising natural compound targeting TOP2A.CONCLUSION:Cumulatively, this study signifies that TOP2A promotes breast cancer progression, and targeting TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance.

Although advances in diagnostics and therapeutics have prolonged the survival of triple-negative breast cancer (TNBC) patients, metastasis, therapeutic resistance, and lack of targeted therapies remain the foremost hurdle in the effective management of TNBC. Thus, evaluation of new therapeutic agents and their efficacy in combination therapy is urgently needed. The third-generation retinoid adapalene (ADA) has potent antitumor activity, and using ADA in combination with existing therapeutic regimens may improve the effectiveness and minimize the toxicities and drug resistance. The current study aimed to assess the anticancer efficacy of adapalene as a combination regimen with the PI3K inhibitor (GDC-0941) in TNBC in vitro models. The Chou-Talalay's method evaluated the pharmacodynamic interactions (synergism, antagonism, or additivity) of binary drug combinations. Flow cytometry, Western blotting, and in silico studies were used to analyze the mechanism of GDC-ADA synergistic interactions in TNBC cells. The combination of GDC and ADA demonstrated a synergistic effect in inhibiting proliferation, migration, and colony formation of tumor cells. Accumulation of reactive oxygen species upon co-treatment with GDC and ADA promoted apoptosis and enhanced sensitivity to GDC in TNBC cells. The findings indicate that ADA is a promising therapeutic agent in treating advanced BC tumors and enhance sensitivity to GDC in inhibiting tumor growth in TNBC models while reducing therapeutic resistance.

Doxorubicin is a commonly used chemotherapeutic agent to treat several malignancies, including aggressive tumors like triple-negative breast cancer. It has a limited therapeutic index owing to its extreme toxicity and the emergence of drug resistance. As a result, there is a pressing need to find innovative drugs that enhance the effectiveness of doxorubicin while minimizing its toxicity. The rationale of the present study is that combining emerging treatment agents or repurposed pharmaceuticals with doxorubicin might increase susceptibility to therapeutics and the subsequent establishment of improved pharmacological combinations for treating triple-negative breast cancer. Additionally, combined treatment will facilitate dosage reduction, reducing the toxicity associated with doxorubicin. Recently, the third-generation retinoid adapalene was reported as an effective anticancer agent in several malignancies. This study aimed to determine the anticancer activity of adapalene in TNBC cells and its effectiveness in combination with doxorubicin, and the mechanistic pathways in inhibiting tumorigenicity. Adapalene inhibits tumor cell growth and proliferation and acts synergistically with doxorubicin in inhibiting growth, colony formation, and migration of TNBC cells. Also, the combination of adapalene and doxorubicin enhanced the accumulation of reactive oxygen species triggering hyperphosphorylation of Erk1/2 and caspase-dependent apoptosis. Our results demonstrate that adapalene is a promising antitumor agent that may be used as a single agent or combined with present therapeutic regimens for TNBC treatment.

Abstract Purpose: Doxorubicin (DOX) is a commonly used chemotherapeutic agent to treat several malignancies, including aggressive tumors like triple negative breast cancer (TNBC) lacking hormonal receptors and HER2 amplification. It has a limited therapeutic index owing to its extreme toxicity and the emergence of drug resistance. As a result, there is a pressing need to find innovative drugs that enhance the effectiveness of doxorubicin while minimizing its toxicity. Recently, the third-generation retinoid adapalene (ADA) was reported as an effective anticancer agent in several malignancies. This study aimed to determine the anticancer activity of ADA in TNBC cells and its effectiveness in combination with DOX and the mechanistic pathways in inhibiting tumorigenicity.Methods: Cell viability was evaluated using the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium (MTT) and pharmacodynamic interactions (synergism, antagonism, or additivity) by Chou-Talalay's method. Flow cytometry and fluorimetry were used to determine apoptosis, cell cycle and reactive oxygen species (ROS). Western blotting was utilized to analyze the molecular mechanism and apoptotic protein levels.Results: We found that ADA in synergistic manner with doxorubicin inhibits growth, colony formation, and migration of TNBC cells. Moreover, ADA as single agent or in combination with DOX resulted in ROS accumulation triggering hyperphosphorylation of Erk1/2 and activating caspase 3 and apoptosis. N-acetyl-L-cysteine (NAC) pre-treatment inhibited ROS accumulation triggered by DOX-ADA and substantially reduced Erk1/2 phosphorylation.Conclusions: Our results demonstrate that ADA is a potent antitumor agent that may be used as a single agent or combined with present therapeutic regimens for TNBC treatment.

TNBC treatment is difficult because of its heterogeneity, aggressive nature, and limited treatment responses. Because there are no unique treatment methods for this tumor subgroup, TNBC is treated with standard therapies, which typically results in systemic relapse. Notwithstanding initial chemotherapeutic responses, resistance emerges commonly and quickly, and metastatic TNBC had a bad prognosis. As a result, more targeted techniques are desperately required. To better comprehend the immunological and molecular features of TNBC, various novel medicines and combination approaches have been investigated. In this chapter, we will discuss current clinical advancements in targeted strategies for TNBC, such as various signaling pathways involved in TNBC treatment, chemotherapeutics, anti-angiogenic treatments, Histone Deacetylase and HSP 90 Inhibitors, anti-angiogenesis therapy, MEK inhibitors, and also novel immune-checkpoint inhibitor-based methods that have lately shown promising results. In addition, we will also discuss the advanced therapeutic options for the TNBC based on miRNAs, lnRNAs, and siRNAs which are an appealing potential for targeted therapy against TNBC.

Presently, breast cancer (BC) is one of the most common malignancies diagnosed and the leading cause of tumor-related deaths among women worldwide. Cell cycle dysregulation is one of the hallmarks of cancer, resulting in uncontrolled cell proliferation. Cyclin-dependent kinases (CDKs) are central to the cell cycle control system, and deregulation of these kinases leads to the development of malignancies, including breast cancer. CDKs and cyclins have been reported as crucial components involved in tumor cell proliferation and metastasis. Given the aggressive nature, tumor heterogeneity, and chemoresistance, there is an urgent need to explore novel targets and therapeutics to manage breast cancer effectively. Inhibitors targeting CDKs modulate the cell cycle, thus throwing light upon their therapeutic aspect where the progression of tumor cells could be inhibited. This article gives a comprehensive account of CDKs in breast cancer progression and metastasis and recent developments in the modulation of CDKs in treating malignancies. We have also explored the expression pattern and prognostic significance of CDKs in breast cancer patients. The article will also shed light on the Implications of CDK inhibition and TGF-β signaling in breast cancer.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking the three hormonal receptors namely estrogen receptor, progesterone receptor and HER2 receptor, and the only treatment option available for TNBC is chemotherapy. Chemotherapy lacks specificity since it acts on normal healthy cells as well resulting into secondary diseases in TNBC patients. In addition chemotherapy poses recurrence and relapse issues due to the development of chemoresistance among TNBC patients. Immunotherapy remarkably immune checkpoint inhibitors show a great therapeutic potential in TNBC. As TNBC contain an increased TILs (tumor infiltrating lymphocytes) infiltration making it more suitable as a therapeutic target anti-tumor immune strategy. Moreover, evidences have indicated that chemotherapy upregulates the anti-tumor immune response in TNBC. As a result, a combination of immunotherapy with chemotherapy may increase the overall relapse and recurrence free survival of TNBC patients. Therefore, in this chapter we will focus on how the immunotherapy works in TNBC, their effects and consequences. We will further be discussing the clinical studies and the importance of immune checkpoint inhibitors (ICIs) in combination with various therapeutic agents and target. Further, we will explore the processes involved.

BACKGROUND Globally, breast cancer (BC) has become one of the most prevalent malignancies and the leading cause of tumor-related deaths among women. Dysregulation of the cell cycle is a well-known hallmark of cancer development and metastasis. CDKs are essential components of the cell-cycle regulatory system with aberrant expression in a variety of cancers, including BC. In the development of targeted cancer treatment, reestablishing the regulation of the cell cycle by modulation of CDKs has emerged as a promising approach. METHODS Herein, we used a bioinformatic approach to assess the expression pattern, prognostic and diagnostic importance, and clinical relevance of CDKs in BC. Additionally, we conducted a functional enrichment analysis of deregulated CDKs using the STRING and KEGG databases to delineate the role of CDKs in breast tumorigenesis. RESULTS Gene expression analysis revealed substantial deregulation of CDKs in BC, with CDK1, CDK11A, and CDK18 showing a fold change of >± 1.5. Also, metastatic tumors showed high expression of CDK1 in the single cell RNA sequencing analysis of primary and metastatic breast tumors. Additionally, it was found that dysregulated CDK expression affects overall survival (OS) and relapse-free survival (RFS) of BC patients. CONCLUSION The study's multimodal analytical methodologies imply that modulating CDKs for BC treatment is a promising approach.

The CDKs are known to play a critical role in cell cycle regulation process. Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer. However, the treatment with palbociclib has shown many associated toxicities such as-anemia, thrombocytopenia, neutropenia, and febrile neutropenia and more. Despite the fact being FDA approved for only breast cancer and no other cancers and CDK4 being overexpressed in multiple cancers. Therefore, we in our study intend to screen two novel CDK4 inhibitors that show considerably less associated toxicities and greater therapeutic implications than palbociclib. We screened the compounds using Lipinski's rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.

BACKGROUND:Breast cancer (BC), one of the most prevalent malignancies, is the second major cause of mortality from cancer among women worldwide. Even though substantial progress has been made in breast cancer treatment, metastasis still accounts for the majority of the deaths. The tumor microenvironment (TME) comprising stromal and non-stromal components is central to tumor growth and development and is partly regulated by chemokines. Chemokines regulate immune cell trafficking, the development of stroma and play a key role in inflammation, a cancer hallmark.METHODS:In the present study, we used a bioinformatics approach to identify highly deregulated chemokines in BC patients. We performed expression analysis, survival analysis, gene ontology analysis, KEGG analysis, and protein-protein interaction network analysis of the deregulated chemokines using Gepia2, UALCAN, Kaplan-Meier Plotter, DAVID, and STRING tools.RESULTS:We identified >2-fold change (FC) increase in CXCL9/10/11/13 and >-2 FC decrease in CCL14/21/28, CXCL2/12 CX3CL1. Also, increased expression of CCL14, CCL21, CXCL13, CXCL9, CXCL12 correlated with better overall survival (OS) of BC patients.CONCLUSIONS:Our results strongly indicate that chemokines may have potential biomarker characteristics, and the constructed PPI network contributed to an in-depth understanding of the chemokine networks. The deregulated chemokines may prove to be therapeutic targets for the effective management of BC.