Targeted reprogramming of tumor-associated macrophages for overcoming glioblastoma resistance to chemotherapy and immunotherapy.

The resistance of glioblastoma multiforme (GBM) to standard chemotherapy is primarily attributed to the existence of tumor-associated macrophages (TAMs) in the GBM microenvironment, particularly the anti-inflammatory M2 phenotype. Targeted modulation of M2-TAMs is emerging as a promising strategy to enhance chemotherapeutic efficacy. However, combination TAM-targeted therapy with chemotherapy faces substantial challenges, notably in terms of delivery efficiency and targeting specificity. In this study, we designed a pH-responsive hierarchical brain-targeting micelleplex loaded with temozolomide (TMZ) and resiquimod (R848) for combination chemo-immunotherapy against GBM. This delivery system, termed PCPA&PPM@TR, features a primary Angiopep-2 decoration on the outer layer via a pH-cleavable linker and a secondary mannose analogue (MAN) on the middle layer. This pH-responsive hierarchical targeting strategy enables effective BBB permeability while simultaneous GBM- and TAMs-targeting delivery. GBM-targeted delivery of TMZ induces alkylation and triggers an anti-GBM immune response. Concurrently, TAM-targeted delivery of R848 reprograms their phenotype from M2 to pro-inflammatory M1, thereby diminishing GBM resistance to TMZ and amplifying the immune response. In vivo studies demonstrated that targeted modulation of TAMs using PCPA&PPM@TR significantly enhanced anti-GBM efficacy. In summary, this study proposes a promising brain-targeting delivery system for the targeted modulation of TAMs to combat GBM.

Chemo-resistant Gestational Trophoblastic Neoplasia and the Use of Immunotherapy: A Case Report and Review of Literature.

This is the first reported case of the use of immunotherapy in chemo-resistant Gestational Trophoblastic Neoplasia (GTN) in the country. A 41-year-old, Gravida 4 Para 3 (3013) with a diagnosis of GTN, Stage III: WHO risk score of 13 (Choriocarcinoma) was initially managed with 10 cycles of multiple agent Etoposide, Methotrexate, Actinomycin D-Cyclophosphomide and Vincristine (EMACO) and 19 cycles of Etoposide, Cisplatin-Etoposide Methotrexate and Actinomycin D (EP-EMA). With continuous rise in beta human chorionic gonadotropin (ßhCG) levels, the patient was referred to a Trophoblastic Disease Center where there was note of tumor progression to the brain. She was started on third-line salvage chemotherapy of Paclitaxel and Carboplatin (PC) with concomitant whole brain irradiation completing three cycles after which chemoresistance was again diagnosed with increasing hCG titers and increase in the number and size of the pulmonary masses which were deemed unresectable. Immunotherapy was started with Pembrolizumab showing a good response with marked fall in ßhCG levels. The onset of immune-related adverse events (irAEs) caused a marked delay in subsequent cycles of immunotherapy. With management of the irAEs, two more cycles of Pembrolizumab with fifty percent dose reduction were given with corresponding drop in ßhCG levels. However, the patient subsequently developed gram-negative septicemia with possible hematologic malignancy and finally succumbed to massive pulmonary embolism. The case highlights the importance of prompt diagnosis and referral to a Trophoblastic Disease Center and the use of immunotherapy in chemo-resistant GTN.

MicroRNAs as the pivotal regulators of Temozolomide resistance in glioblastoma.

Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.

Energy stress-activated AMPK phosphorylates Snail1 and suppresses its stability and oncogenic function.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therapeutic responses and TNBC-related death. However, the underlying mechanisms are not fully understood. In this study, we delineate a previously unrecognized role of aberrant glucose metabolism in regulating the turnover of Snail1, which is a key transcriptional factor of epithelial-mesenchymal transition (EMT) and critically contributes to the acquisition of stemness, metastasis and chemo-resistance. Mechanistically, we demonstrate that AMP-activated protein kinase (AMPK), when activated in response to glucose deprivation, directly phosphorylates Snail1 at Ser11. Such a phosphorylation modification of Snail1 facilitates its recruitment of the E3 ligase FBXO11 and promotes its degradation, thereby suppressing stemness, metastasis and increasing cellular sensitivity to chemotherapies in vitro and in vivo. Clinically, histological analyses reveal a negative correlation between p-AMPKα and Snail1 in TNBC specimens. Taken together, our findings establish a novel mechanism and functional significance of AMPK in linking glucose status to Snail1-dependent malignancies and underscore the potential of AMPK agonists as a promising therapeutic strategy in the management of TNBC.

Critical role of miR-21/exosomal miR-21 in autophagy pathway.

Activation of autophagy, a process of cellular stress response, leads to the breakdown of proteins, organelles, and other parts of the cell in lysosomes, and can be linked to several ailments, such as cancer, neurological diseases, and rare hereditary syndromes. Thus, its regulation is very carefully monitored. Transcriptional and post-translational mechanisms domestically or in whole organisms utilized to control the autophagic activity, have been heavily researched. In modern times, microRNAs (miRNAs) are being considered to have a part in post-translational orchestration of the autophagic activity, with miR-21 as one of the best studied miRNAs, it is often more than expressed in cancer cells. This regulatory RNA is thought to play a major role in a plethora of processes and illnesses including growth, cancer, cardiovascular disease, and inflammation. Different studies have suggested that a few autophagy-oriented genes, such as PTEN, Rab11a, Atg12, SIPA1L2, and ATG5, are all targeted by miR-21, indicating its essential role in the regulation.

Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights.

Oral squamous cell carcinoma (OSCC) is a cancer type with a high rate of recurrence and a poor prognosis. Tumor chemo-resistance remains an issue for OSCC patients despite the availability of multimodal therapy options, which causes an increase in tumor invasiveness. Vacuolar ATPase (V-ATPase), appears to be one of the most significant molecules implicated in MDR in tumors like OSCC. It is primarily responsible for controlling the acidity in the solid tumors' microenvironment, which interferes with the absorption of chemotherapeutic medications. However, the exact cellular and molecular mechanisms V-ATPase plays in OSCC chemo-resistance have not been understood. Uncovering these mechanisms can contribute to combating OSCC chemo-resistance and poor prognosis. Hence, in this review, we suggest that one of these underlying mechanisms is autophagy induced by V-ATPase which can potentially contribute to OSCC chemo-resistance. Finally, specialized autophagy and V-ATPase inhibitors may be beneficial as an approach to reduce drug resistance to anticancer therapies in addition to serving as coadjuvants in antitumor treatments. Also, V-ATPase could be a prognostic factor for OSCC patients. However, in the future, more investigations are required to demonstrate these suggestions and hypotheses.

[Retracted] Chronic oxymatrine treatment induces resistance and epithelial­mesenchymal transition through targeting the long non­coding RNA MALAT1 in colorectal cancer cells.

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the cell migration and invasion assay data featured in Figs. 2B, 5C, 6B and C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been submitted elsewhere prior to the submission of this paper to Oncology Reports, or were under consideration for publication at around the same time (one of which has been retracted). In view of the fact that certain of these data had already apparently been submitted for publication prior to the submission of this article to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 967­976, 2018; DOI: 10.3892/or.2018.6204].

YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer.

The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC50) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program's role in chemotherapy resistance paves the way for YAP therapeutic targeting.

Unravelling the role of Silibinin in targeting CD44+ cancer stem cells: Therapeutic implications, effective strategies and approaches.

CD44+ cancer stem cells (CSCs) are believed to account for drug resistance and tumour recurrence due to their potential to self-renew and differentiate into heterogeneous lineages. Therefore, efficient treatment strategies targeting and eliminating these CSCs are required. The flavonolignan, Silibinin, has gained immense attention in targeting CD44+ CSCs as it alters functional properties like cell cycle arrest, apoptosis, inhibition of invasion and metastasis and also inhibits a range of molecular pathways. However, its limited bioavailability is a major hurdle in asserting Silibinin as a translational therapeutic agent. Combinatorial therapy of Silibinin with conventional chemotherapeutic drugs is an alternative approach in targeting CD44+ CSCs as it increases the efficacy and reduces the cytotoxicity of chemotherapeutic drugs, thus preventing drug resistance. Certain Silibinin-conjugated nano-formulations have also been successfully developed, through which there is improved absorptivity/bioavailability of Silibinin and a decrease in the concentration of therapeutic drugs leading to reduced cytotoxicity. In this review, we summarise the effectiveness of the synergistic therapeutic approach for Silibinin in targeting the molecular mechanisms of CD44+ CSCs and emphasise the potential role of Silibinin as a novel therapeutic agent.

Scaffold hopping for designing of potent and selective CYP1B1 inhibitors to overcome docetaxel resistance: synthesis and evaluation.

Cytochrome P450 1B1, a tumor-specific overexpressed enzyme, significantly impairs the pharmacokinetics of several commonly used anticancer drugs including docetaxel, paclitaxel and cisplatin, leading to the problem of resistance to these drugs. Currently, there is no CYP1B1 inhibition-based adjuvant therapy available to treat this resistance problem. Hence, in the current study, exhaustive in-silico studies including scaffold hopping followed by molecular docking, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular dynamics and free energy perturbation studies were carried out to identify potent and selective CYP1B1 inhibitors. Initially, scaffold hopping analysis was performed against a well-reported potent and selective CYP1B1 inhibitor (i.e. compound 3n). A total of 200 scaffolds were identified along with their shape and field similarity scores. The top three scaffolds were further selected on the basis of these scores and their synthesis feasibility to design some potent and selective CYP1B1 inhibitors using the aforementioned in-silico techniques. Designed molecules were further synthesized to evaluate their CYP1B1 inhibitory activity and docetaxel resistance reversal potential against CYP1B1 overexpressed drug resistance MCF-7 cell line. In-vitro results indicated that compounds 2a, 2c and 2d manifested IC50 values for CYP1B1 ranging from 0.075, 0.092 to 0.088 µM with at least 10-fold selectivity. At low micromolar concentrations, compounds 1e, 1f, 2a and 2d exhibited promising cytotoxic effects in the docetaxel-resistant CYP1B1 overexpressed MCF-7 cell line. In particular, compound 2a is most effective in reversing the resistance with IC50 of 29.0 ± 3.6 µM. All of these discoveries could pave the way for the development of adjuvant therapy capable of overcoming CYP1B1-mediated resistance.Communicated by Ramaswamy H. Sarma.

Cannabigerol Induces Autophagic Cell Death by Inhibiting EGFR-RAS Pathways in Human Pancreatic Ductal Adenocarcinoma Cell Lines.

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis associated with this cancer is due to the absence of specific biomarkers, aggressiveness, and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that result in cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory properties. Regarding the anticancer effect of CBG, up to now, there is only limited evidence in human cancers. To fill this gap, we investigated the effects of CBG on the PDAC cell lines, PANC-1 and MIAPaCa-2. The effect of CBG activity on cell viability, cell death, and EGFR-RAS-associated signaling was investigated. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate the effect of CBG on PDAC cell line viabilities. Annexin-V and Acridine orange staining, followed by cytofluorimetric analysis and Western blotting, were used to evaluate CBG's effect on cell death. The modulation of EGFR-RAS-associated pathways was determined by Western blot analysis and a Milliplex multiplex assay. Moreover, by employing the MTT data and SynergyFinder Plus software analysis, the effect of the combination of CBG and chemotherapeutic drugs was determined.

Targeting Cervical Cancer Stem Cells by Phytochemicals.

Cervical cancer (CaCx) poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide. Despite the emergence of advanced treatment strategies, recurrence remains a bottleneck in favorable treatment outcomes and contributes to poor prognosis. The chemo- or radio-therapy resistance coupled with frequent relapse of more aggressive tumors are some key components that contribute to CaCx-related mortality. The onset of therapy resistance and relapse are attributed to a small subset of, slow-proliferating Cancer Stem Cells (CSC). These CSCs possess the properties of tumorigenesis, self-renewal, and multi-lineage differentiation potential. Because of slow cycling, these cells maintain themselves in a semi-quiescent stage and protect themselves from different anti-proliferative anti-cancer drugs. Keeping in view recent advances in their phenotypic and functional characterization, the feasibility of targeting CSC and associated stem cell signaling bears a strong translational value. The presence of CSC has been reported in CaCx (CCSC) which remains a forefront area of research. However, we have yet to identify clinically useful leads that can target CCSC. There is compelling evidence that phytochemicals, because of their advantages over synthetic anticancer drugs, could emerge as potential therapeutic leads to target these CCSCs. The present article examined the potential of phytochemicals with reported anti-CSC properties and evaluated their future in preclinical and clinical applications against CaCx.

Nicotine promotes epithelial to mesenchymal transition and gemcitabine resistance via hENT1/RRM1 signalling in pancreatic cancer and chemosensitizing effects of Embelin-a naturally occurring benzoquinone.

Pancreatic cancer is lethal due to poor prognosis with 5-year survival rate lesser than 5 %. Gemcitabine is currently used to treat pancreatic cancer and development of chemoresistance is a major obstacle to overcome pancreatic cancer. Nicotine is a known inducer of drug resistance in pancreatic tumor micro-environment. Present study evaluates chemoresistance triggered by nicotine while treating with gemcitabine and chemosensitization using Embelin. Embelin is a naturally occurring benzoquinone from Embelia ribes possessing therapeutic potency. To develop nicotine-induced chemo-resistance, pancreatic cancer cells PANC-1 and MIA PaCa-2 were continuously treated with nicotine followed by exposure to gemcitabine. Gemcitabine sensitivity assay and immunoblotting was performed to assess the chemo-resistance. Antiproliferative assays such as migration assay, clonogenic assay, Mitochondrial Membrane Potential (MMP) assay, dual staining assay, comet assay, Reactive Oxygen Species (ROS) assay, cell cycle analysis and immunoblotting assays were performed to witness the protein expression involved in chemoresistance and chemosensitization. Epithelial to mesenchymal transition was observed in nicotine induced chemoresistant cells. Gemcitabine sensitivity assay revealed that relative resistance was increased to 6.26 (p < 0.0001) and 6.45 (p < 0.0001) folds in resistant PANC-1 and MIA PaCa-2 compared to parental cells. Protein expression studies confirmed resistance markers like hENT1 and dCK were downregulated with subsequent increase in RRM1 expression in resistant cells. Embelin considerably decreased the cell viability with an IC50 value of 4.03 ± 0.08 µM in resistant PANC-1 and 2.11 ± 0.04 µM in resistant MIA PaCa-2. Cell cycle analysis showed Embelin treatment caused cell cycle arrest at S phase in resistant PANC-1 cells; in resistant MIA PaCa-2 cells there was an escalation in the Sub G1. Embelin upregulated Bax, γH2AX, p53, ERK1/2 and hENT1 expression with concomitant down regulation of Bcl-2 and RRM1. Bioactive molecule embelin, its combination with gemcitabine could provide new vistas to overcome chemo resistance in pancreatic cancer.

Therapeutic antibodies for the prevention and treatment of cancer.

The developments of antibodies for cancer therapeutics have made remarkable success in recent years. There are multiple factors contributing to the success of the biological molecule including origin of the antibody, isotype, affinity, avidity and mechanism of action. With better understanding of mechanism of cancer progression and immune manipulation, recombinant formats of antibodies are used to develop therapeutic modalities for manipulating the immune cells of patients by targeting specific molecules to control the disease. These molecules have been successful in minimizing the side effects instead caused by small molecules or systemic chemotherapy but because of the developing therapeutic resistance against these antibodies, combination therapy is thought to be the best bet for patient care. Here, in this review, we have discussed different aspects of antibodies in cancer therapy affecting their efficacy and mechanism of resistance with some relevant examples of the most studied molecules approved by the US FDA.

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling.

Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.

Promising applications of nanotechnology in inhibiting chemo-resistance in solid tumors by targeting epithelial-mesenchymal transition (EMT).

The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.

Zinc Oxide Nanoparticles and Cancer Chemotherapy: Helpful Tools for Enhancing Chemo-sensitivity and Reducing Side Effects?

Cancer chemotherapy is still a serious challenge. Chemo-resistance and destructive side effects of chemotherapy drugs are the most critical limitations of chemotherapy. Chemo-resistance is the leading cause of chemotherapy failure. Chemo-resistance, which refers to the resistance of cancer cells to the anticancer effects of chemotherapy drugs, is caused by various reasons. Among the most important of these reasons is the increase in the efflux of chemotherapy drugs due to the rise in the expression and activity of ABC transporters, the weakening of apoptosis, and the strengthening of stemness. In the last decade, a significant number of studies focused on the application of nanotechnology in cancer treatment. Considering the anti-cancer properties of zinc, zinc oxide nanoparticles have received much attention in recent years. Some studies have indicated that zinc oxide nanoparticles can target the critical mechanisms of cancer chemo-resistance and enhance the effectiveness of chemotherapy drugs. These studies have shown that zinc oxide nanoparticles can reduce the activity of ABC transporters, increase DNA damage and apoptosis, and attenuate stemness in cancer cells, leading to enhanced chemo-sensitivity. Some other studies have also shown that zinc oxide nanoparticles in low doses can be helpful in minimizing the harmful side effects of chemotherapy drugs. In this article, after a brief overview of the mechanisms of chemo-resistance and anticancer effects of zinc, we will review all these studies in detail.

Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor) distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.

Molecular docking analysis of triterpenoids from Cassia fistula with breast cancer targets.

Breast cancer is a well-known complex disease. The availability of different screening approaches and booming phytochemical drug synthesis can contribute towards breast cancer treatment. Hence, we document the molecular docking analysis of triterpenoids from Cassia fistula with breast cancer targets.

Expression of YAP suppresses cell proliferation and elevates the sensitivity of chemotherapy in retinoblastoma cells through lipid-peroxidation induced ferroptosis.

BACKGROUND: Retinoblastoma (RB) is a retinal cancer most commonly occurred in young children. Cisplatin and etoposide had been confirmed as chemotherapy drugs in the treatment of RB, even though the phenomenon of chemotherapeutic resistance has been occurring in clinical treatment frequently. RB has been reported to be a tumor with reduced expression of yes-associated protein (YAP). However, the role of YAP protein and its correlation with the chemotherapy effect in RB still remains unknown. METHODS: Here we used human RB cell lines Y79 and RB3823 to construct YAP over-expression cell lines for exploring the specific role of YAP. In vitro, a series of techniques and methods were used to identify the biological role of YAP in RB, such as Agilent Seahorse assay, lipid peroxidation assay, intracellular reactive oxygen species (ROS) measurement, flow cytometry apoptosis assay, and other basic experimental techniques, among others. RESULTS: The cell growth and cytology experimental results found YAP can inhibit the proliferation of RB cells and promote their apoptosis (Y79 32.71% vs. 3.75%; RB3823 40.32% vs. 6.73%). The mitochondrial fuel flex test, lipid peroxide and ROS measurement confirmed that YAP over-expression could promote mitochondrial fatty-acids ß-oxidation and lipid peroxidation in RB cells. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the expression of lipid peroxidation related factors imply that YAP over-expression caused ferroptosis in RB cell lines. In addition, YAP transcription specific activator PY-60 (10 µM) further improved the sensitivity of cisplatin/etoposide. CONCLUSIONS: Our research results found the expression of YAP inhibits cell proliferation and promoted lipid peroxidation induced ferroptosis in RB. Interestingly, the mitochondrial oxidative phosphorylation shows an increased fatty acid dependency and decreased glucose dependency. As a result, this phenomenon improved the sensitivity of RB to cisplatin/etoposide chemotherapy in vitro. Our finding provides a potential therapeutic target for RB chemotherapy.