Chemotherapeutic Combinations Research Articles

Exosome-sheathed porous silica nanoparticle-mediated co-delivery of 3,3′-diindolylmethane and doxorubicin attenuates cancer stem cell-driven EMT in triple negative breast cancer

BackgroundTherapeutic management of locally advanced and metastatic triple negative breast cancer (TNBC) is often limited due to resistance to conventional chemotherapy. Metastasis is responsible for more than 90% of breast cancer-associated mortality; therefore, the clinical need to prevent or target metastasis is immense. The epithelial to mesenchymal transition (EMT) of cancer stem cells (CSCs) is a crucial determinant in metastasis. Doxorubicin (DOX) is the frequently used chemotherapeutic drug against TNBC that may increase the risk of metastasis in patients. After cancer treatment, CSCs with the EMT characteristic persist, which contributes to advanced malignancy and cancer recurrence. The latest developments in nanotechnology for medicinal applications have raised the possibility of using nanomedicines to target these CSCs. Hence, we present a novel approach of combinatorial treatment of DOX with dietary indole 3,3′-diindolylmethane (DIM) which is an intriguing field of research that may target CSC mediated EMT induction in TNBC. For efficient delivery of both the compounds to the tumor niche, advance method of drug delivery based on exosomes sheathed with mesoporous silica nanoparticles may provide an attractive strategy.ResultsDOX, according to our findings, was able to induce EMT in CSCs, making the breast cancer cells more aggressive and metastatic. In CSCs produced from spheres of MDAMB-231 and 4T1, overexpression of N-cadherin, Snail, Slug, and Vimentin as well as downregulation of E-cadherin by DOX treatment not only demonstrated EMT induction but also underscored the pressing need for a novel chemotherapeutic combination to counteract this detrimental effect of DOX. To reach this goal, DIM was combined with DOX and delivered to the CSCs concomitantly by loading them in mesoporous silica nanoparticles encapsulated in exosomes (e-DDMSNP). These exosomes improved the specificity, stability and better homing ability of DIM and DOX in the in vitro and in vivo CSC niche. Furthermore, after treating the CSC-enriched TNBC cell population with e-DDMSNP, a notable decrease in DOX mediated EMT induction was observed.ConclusionOur research seeks to propose a new notion for treating TNBC by introducing this unique exosomal nano-preparation against CSC induced EMT.Graphical

Synchronized Codelivery of Combination Chemotherapies Intratumorally Using a Lipidic Lyotropic Liquid Crystal System.

In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy.

Dual Drug Delivery in Cancer Therapy Using Graphene Oxide‐Based Nanoplatforms

Many types of cancer are currently treated using a combination of chemotherapeutics, but unfortunately, this strategy is considerably limited by severe side effects. The current development of nanocarriers enables the use of multiple drugs anchored on one unique platform thus enhancing the initiated therapeutic effect and minimizing the possibility of drug resistance. In this context, a graphene‐oxide‐based 2D nanoplatform is developed, which is functionalized using highly branched polyethylene‐glycol and a multimodal set of two drugs with various mechanisms of action, namely Pt‐based complex (a Pt(IV) prodrugs based on cisplatin) and doxorubicin (DOX). We performed in vitro 2D screening on two cancer cell lines, namely glioblastoma and osteosarcoma, that were selected as models of two aggressive tumors that remain a massive challenge in oncology. The therapeutic effect of the developed nano‐platform is higher at lower concentrations (15 μm of Pt‐drug, 0.6 μm DOX) compared to the impact of the free drugs. This indicates a possible positive effect of the accumulation and transport of the drugs using this nanoplatform. Results obtained on 3D cell models using MG63 osteosarcoma cells uncovered an understandable lowered diffusion profile of the developed nanoplatforms, compared to the application of free drugs.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

Reversing Anticancer Drug Resistance by Synergistic Combination of Chemotherapeutics and Membranolytic Antitumor β-Peptide Polymer.

Multidrug resistance is the main obstacle to cancer chemotherapy. Overexpression of drug efflux pumps causes excessive drug efflux from cancer cells, ultimately leading to drug resistance. Hereby, we raise an effective strategy to overcome multidrug resistance using a synergistic combination of membranolytic antitumor β-peptide polymer and chemotherapy drugs. This membrane-active β-peptide polymer promotes the transmembrane transport of chemotherapeutic drugs by increasing membrane permeability and enhances the activity of chemotherapy drugs against multidrug-resistant cancer cells. As a proof-of-concept demonstration, the synergistic combination of β-peptide polymer and doxorubicin (DOX) is substantially more effective than DOX alone against drug-resistant cancer both in vitro and in vivo. Notably, the synergistic combination maintains a potent anticancer activity after continuous use. Collectively, this combination therapy using membrane lytic β-peptide polymer appears to be an effective strategy to reverse anticancer drug resistance.

British Oncology Pharmacy Association Delphi consensus guidelines: Co-infusion of trometamol-containing calcium folinate (Leucovorin) with systemic anti-cancer treatments.

Drug stability and compatibility are critical factors influencing the cost and logistics of treatment delivery, therapeutic effectiveness, and patient safety. This is particularly significant in the realm of cancer chemotherapeutics, where stability and compatibility studies play a vital role in ensuring rational and safe medicine administration. Oxaliplatin, fluorouracil, and irinotecan, commonly used in various combinations for gastrointestinal cancers, are complemented by co-administration of folinic acid in certain protocols. Notably, some folinic acid preparations include trometamol as an excipient, potentially impacting the stability of the chemotherapeutic agents if infused concomitantly. This study seeks to establish guidelines for oncology multidisciplinary teams, addressing potential risks associated with the combination of trometamol-containing folinic acid and chemotherapeutics. To achieve this, a quantitative questionnaire was distributed to members of the British Oncology Pharmacy Association (BOPA) and non-BOPA members through an online survey. Nineteen healthcare professionals with oncology experience, comprising 18 pharmacists and one nurse, completed the questionnaires. Each participant rated the validity and clarity of statements on a 5-point scale. The Delphi process concluded after the fourth round, consolidating the findings and recommendations from the multidisciplinary team. Twelve recommendations for safe practice have been made.

Metformin and buparlisib synergistically induce apoptosis of non-small lung cancer (NSCLC) cells via Akt/FoxO3a/Puma axis

Non-small cell lung cancer (NSCLC) is a global health issue lacking effective treatments. Buparlisib is a pan-PI3K inhibitor that shows promising clinical results in treating NSCLC. However, chemoresistance is inevitable and hampers the application of buparlisib. Studies show that a combination of phytochemicals and chemotherapeutics enhances its effectiveness. Here, we evaluated the role of metformin, an agent with multiple pharmacological properties, in enhancing the anti-tumour activities of buparlisib against NSCLC cells. Our results showed that metformin and buparlisib synergistically inhibited cell viability, migration, and invasion of NSCLC cells. In addition, co-treatment of metformin and buparlisib also induced cell cycle arrest and cell death in NSCLC cells. Mechanistically, metformin and buparlisib repressed Mcl-1 and upregulated Puma in NSCLC cells in a p53-independent manner. Moreover, they inhibited the PI3K/Akt signalling pathway, leading to activation of the FoxO3a/Puma signalling in NSCLC cells. Our findings suggest that combined treatment of metformin and buparlisib might provide a promising strategy for treating NSCLC.

Development of Aerosol Dry Powder Chemotherapeutic-Loaded Microparticles for the Treatment of Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide, resulting in the highest mortality rates among both men and women with respect to all other types of cancer. Difficulties in treating lung cancer arise from late-stage diagnoses and tumor heterogeneity and current treatment involves a combination of chemotherapeutics, surgery, and radiation. Chemotherapeutics administered systemically can lead to undesirable side effects and severe off-site toxicity. For example, chronic administration of the chemotherapeutic doxorubicin (DOX) leads to cardiotoxicity, thereby limiting its long-term use. Systemic administration of the highly lipophilic molecule paclitaxel (PTX) is hindered by its water solubility, necessitating the use of solubilizing agents, which can induce side effects. Thus, in this investigation, formulations consisting of spray-dried microparticles (MP) containing DOX and PTX were produced to be administered as dry powder aerosols directly to the lungs. Acetalated dextran (Ac-Dex) was used as the polymer in these formulations, as it is a biocompatible and biodegradable polymer that exhibits pH-responsive degradation. Solid-state characterization revealed that DOX and PTX remained in solubility favoring amorphous states in the MP formulations and that both drugs remained thermally stable throughout the spray drying process. In vitro release studies demonstrated the pH sensitivity of the formulations due to the use of Ac-Dex, as well as the release of both therapeutics over the course of at least 48 h. In vitro aerosol dispersion studies demonstrated that both formulations exhibited suitable aerosol dispersion properties for deep lung delivery.Graphical

Andrographolide reverts multidrug resistance in KBChR 8-5 cells through AKT signaling pathway.

Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P-glycoprotein (P-gp) one of the ATP-binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug-resistant KBChR 8-5 cells. Andro exhibited increased cytotoxicity in a concentration-dependent manner in the P-gp overexpressing KBChR 8-5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug-resistant cells. Andro co-administration enhanced PTX- and DOX-induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug-resistant cells. Furthermore, Andro and PTX-induced cell cycle arrest was observed in the drug-resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug-resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P-gp-mediated MDR in KBChR 8-5 cells which might be due to regulating ABCB1/AKT signaling pathway.

Monitoring the Intracellular pH and Metabolic State of Cancer Cells in Response to Chemotherapy Using a Combination of Phosphorescence Lifetime Imaging Microscopy and Fluorescence Lifetime Imaging Microscopy.

The extracellular matrix (ECM), in which collagen is the most abundant protein, impacts many aspects of tumor physiology, including cellular metabolism and intracellular pH (pHi), as well as the efficacy of chemotherapy. Meanwhile, the role of collagen in differential cell responses to treatment within heterogeneous tumor environments remains poorly investigated. In the present study, we simultaneously monitored the changes in pHi and metabolism in living colorectal cancer cells in vitro upon treatment with a chemotherapeutic combination, FOLFOX (5-fluorouracil, oxaliplatin and leucovorin). The pHi was followed using the new pH-sensitive probe BC-Ga-Ir, working in the mode of phosphorescence lifetime imaging (PLIM), and metabolism was assessed from the autofluorescence of the metabolic cofactor NAD(P)H using fluorescence lifetime imaging (FLIM) with a two-photon laser scanning microscope. To model the ECM, 3D collagen-based hydrogels were used, and comparisons with conventional monolayer cells were made. It was found that FOLFOX treatment caused an early temporal intracellular acidification (reduction in pHi), followed by a shift to more alkaline values, and changed cellular metabolism to a more oxidative state. The presence of unstructured collagen markedly reduced the cytotoxic effects of FOLFOX, and delayed and diminished the pHi and metabolic responses. These results support the observation that collagen is a factor in the heterogeneous response of cancer cells to chemotherapy and a powerful regulator of their metabolic behavior.

Combinatorial Optimization of Chemotherapeutic Agents on T-Cell Acute Lymphoblastic Leukemia

Introduction: Up to now, treatment options for T-cell acute lymphoblastic leukemia (T-ALL) remain quite limited. This study aims to assess the efficacy of monotherapies and combination of chemotherapeutic agents for T-ALL. Jurkat, CCRF-CEM are late T-cell progenitor (LTP) cell lines, while Loucy is early T-cell progenitor (ETP) cell line characterized by an immature phenotype. The drugs under evaluation include venetoclax, a selective BCL-2 inhibitor; cytarabine, a cytosine analog with established antineoplastic activity; bendamustine, an alkylating agent; and azacitidine, a DNA methyltransferase inhibitor. Given the notable tumor heterogeneity observed in T-ALL, the comprehensive assessment of these therapeutic agents on Jurkat, CCRF-CEM, and Loucy may render valuable insights for treatment strategies in T-ALL. Methods: Cell lines were cultured in RPMI-1640 medium supplemented with 10% FBS and 1% penicillin-streptomycin at 37°C with 5% CO2. Venetoclax, bendamustine, and azacitidine were prepared as stock solutions in DMSO, while cytarabine was prepared in distilled water. Monotherapies (venetoclax, cytarabine, bendamustine and azacitidine) and combination therapies (venetoclax plus cytarabine, venetoclax plus bendamustine and venetoclax plus azacitidine) were administered. A control group received DMSO or distilled water only. Cell viability was assessed after 48 hours by using Trypan blue and colorimetric method (MTS assay) on cells treated with various drug concentrations. Statistical analysis was conducted using the SynergyFinder Plus and drc R package, with significance set at p < 0.05. Results: Our study demonstrated that T-ALL cell lines displayed a different pattern of drug sensitivities according to combination of chemotherapeutic agents. Loucy showed greater sensitivity to venetoclax while Jurkat and CCRF-CEM exhibited higher sensitivity to cytarabine, bendamustine, and azacitidine. When conducting drug combinations on Jurkat and CCRF-CEM, the addition of venetoclax to cytarabine, bendamustine, or azacitidine resulted in an additive effect, with Loewe synergic scores ranging from -10 to 10 for each combination. On the other hand, Loucy demonstrated a distinct pattern of response; the combination of venetoclax with cytarabine showed additivity (Loewe synergic score: 8.45 and 5.82 with MTS and trypan blue assays, respectively), while venetoclax combined with bendamustine or azacitidine showed a synergistic effect (Loewe synergic score > 10 with MTS assay). Notably, among these combination treatments on Loucy, the pairing of venetoclax with bendamustine showed the most significant synergistic effects, with a Loewe score of 16.6. Conclusion: Venetoclax-based chemotherapeutic combinations exhibited various responses in T-ALL cell lines. Of note, the combination of venetoclax plus bendamustine showed potent synergistic effects in all T-ALL cell lines. These findings warrant further study to develop fundamentally curative therapeutic strategies in T-ALL.

An Optimized Method to Culture Human Primary Lung Tumor Cell Spheroids

Lung cancer is the leading cause of cancer mortality worldwide, with a median survival rate at 5 years of less than 20%. While molecular mapping aids in selecting appropriate therapies, it cannot predict personalized treatment response and long-term efficacy. For addressing these challenges, there is a great need for functional tests. Within this context, we developed patient-derived spheroids (PDS) from tumor and adjacent normal tissue to biomimic the respective tissue for assessing the personalized drug treatment response in vitro. Surgically resected lung specimens were used to generate spheroids using a two-step culture procedure. Flow cytometry and immune staining enabled the characterization of different cell populations resulting from the lung samples. PDS phenotype, cell proliferation and apoptosis were evaluated. Differential gene expression between tumor and adjacent normal tissue was analyzed via RT-qPCR. PDS drug sensitivity was assessed using a cell metabolic assay in response to two chemotherapeutic drug combinations. Cellular and molecular analysis revealed the proportion of epithelial cells, fibroblasts, and immune cells in the patients’ tissue samples. Subsequently, PDS models from tumor and normal lung were successfully established using the expanded epithelial cells. As a proof of concept, an analysis of the drug treatment using PDS of lung adenoid cystic carcinoma exhibited a dose-dependent effect in response to cisplatin/etoposide and cisplatin/paclitaxel. Our spheroid model of both tumor and non-tumor lung cells holds great promise for enhancing the treatment efficacy in the cancer patients.

OGC P43 Is surgery (gastrectomy) alone more effective than surgery combined with adjuvant chemotherapy for the treatment of Stage I-III gastric adenocarcinoma?

Abstract Background Gastric adenocarcinoma, the malignant proliferation of glandular cells in stomach epithelium, is a type of gastric cancer with statistical disease-burden of the 5th most common global and 17th most common cancer in the UK. Gastric adenocarcinoma at different stages (Stage I-IV) present with different prognoses. Particularly promising subset is patients with Stage I-III gastric adenocarcinoma, presenting with 5-year survival rates up to 71.8%, warranting early diagnosis and effective treatment can be vital. There are several treatment modalities, currently surgery being gold-standard. However, understanding pathological nature of tumour development, combination treatments, such as adjuvant chemotherapy after surgery can maximise patient outcomes. Methods The study aimed to investigate patients with Stage I-III (non-advanced) gastric adenocarcinoma, in understanding whether adjuvant chemotherapy combined with surgery provides (1) greater disease-free/disease-specific/cause-specific survival, (2) overall survival, (3) decreased recurrence rates or improved recurrence-free survival, compared to surgery alone. 17 (3 randomised-control, 10 cohort, 4 case-control) English-language, full-text, Level I-III, peer-reviewed studies from MEDLINE and Embase databases, in past 10 years were reviewed. No age/sex/ethnicity/country restrictions applied and dimension of interest limited to Stage I-III gastric adenocarcinoma patients who had undergone tumour resection via surgery, and received chemotherapy as the only adjuvant therapy. Results 7/17 (41.2%) of studies have at least one statistical outcome measure (DFS/OS/RFS, measured by p-values and HR/OR) that supports, with statistical significance, that adjuvant chemotherapy combined with surgery has benefit over surgery alone for the treatment of Stage I-III gastric adenocarcinoma. Majority of studies, 10/17 (58.8%) do not show statistically significant benefit of adjuvant chemotherapy. Conclusions In conclusion, findings of this study are limited by sample size and bias present in individual studies reviewed. Thus, findings are different when compared to prior large-scale meta-analyses and ongoing research is needed in the field (with consideration to advances in interventions i.e. surgical technique and new chemotherapeutic combinations) to fully understand whether adjuvant chemotherapy is effective when combined with surgery for treatment of gastric adenocarcinoma.

Effect of Thymoquinone on Ovarian Carcinoma Cell Viability (OVCAR-3)

Aim: Ovarian cancer is the third most common gynecological malignancy worldwide. However, it has the highest mortality rate among cancers due to its asymptomatic course, late diagnosis and recurrence. Doxorubicin (Dox) is one of the most commonly prescribed chemotherapeutics in the treatment of ovarian and breast cancer. The serious side effects of chemotherapeutic drugs and the development of drug resistance restrict the use of these drugs. The use of natural products with anticancer activity may help partially overcome these problems. In this study, the effects of thymoquinone (TQ) and Dox, a powerful chemotherapy agent, on cell growth inhibition and cell viability on OVCAR-3 and human skin keratinocyte cell line (HaCaT) were determined by the MTT method.
 Method: Ovarian adenocarcinoma cell lines OVCAR-3 (CCL-2™) and HaCat (RRID: CVCL_0038) were used in the study. To determine the IC50 (inhibitory concentration) doses of Dox and TQ, HeLa and HaCaT cell lines were cultivated with the help of an automatic multipipet. Then, MTT test was applied to analyze cell survival (viability).
 Results: OVCAR-3 cell growth was approximately 2.12 nM at the 48th hour in cells treated with Dox, while the IC50 value of TQ at the 48th hour was found to be 62.9 µM.
 Conclusion: These results show that TQ potentiates the effect of Dox and the Dox/TQ combination may be a promising alternative to other chemotherapeutic combinations in the treatment of ovarian cancer with lower side effects.
 Keywords: Thymoquinone, Cancer, Ovarian adenocarcinoma, MTT

Integrative bioinformatics analysis of WDHD1: a potential biomarker for pan-cancer prognosis, diagnosis, and immunotherapy

BackgroundAlthough WD repeat and high-mobility group box DNA binding protein 1 (WDHD1) played an essential role in DNA replication, chromosome stability, and DNA damage repair, the panoramic picture of WDHD1 in human tumors remains unclear. Hence, this study aims to comprehensively characterize WDHD1 across 33 human cancers.MethodsBased on publicly available databases such as TCGA, GTEx, and HPA, we used a bioinformatics approach to systematically explore the genomic features and biological functions of WDHD1 in pan-cancer.ResultsWDHD1 mRNA levels were significantly increased in more than 20 types of tumor tissues. Elevated WDHD1 expression was associated with significantly shorter overall survival (OS) in 10 tumors. Furthermore, in uterine corpus endometrial carcinoma (UCEC) and liver hepatocellular carcinoma (LIHC), WDHD1 expression was significantly associated with higher histological grades and pathological stages. In addition, WDHD1 had a high diagnostic value among 16 tumors (area under the ROC curve [AUC] > 0.9). Functional enrichment analyses suggested that WDHD1 probably participated in many oncogenic pathways such as E2F and MYC targets (false discovery rate [FDR] < 0.05), and it was involved in the processes of DNA replication and DNA damage repair (p.adjust < 0.05). WDHD1 expression also correlated with the half-maximal inhibitory concentrations (IC50) of rapamycin (4 out of 10 cancers) and paclitaxel (10 out of 10 cancers). Overall, WDHD1 was negatively associated with immune cell infiltration and might promote tumor immune escape. Our analysis of genomic alterations suggested that WDHD1 was altered in 1.5% of pan-cancer cohorts and the “mutation” was the predominant type of alteration. Finally, through correlation analysis, we found that WDHD1 might be closely associated with tumor heterogeneity, tumor stemness, mismatch repair (MMR), and RNA methylation modification, which were all processes associated with the tumor progression.ConclusionsOur pan-cancer analysis of WDHD1 provides valuable insights into the genomic characterization and biological functions of WDHD1 in human cancers and offers some theoretical support for the future use of WDHD1-targeted therapies, immunotherapies, and chemotherapeutic combinations for the management of tumors.

Oral chemotherapeutic agents in metastatic hormone-sensitive prostate cancer: A network meta-analysis of randomized controlled trials.

Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents. We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate. We identified 18 RCTs (n=13,509). Concerning OS, ADT+abiraterone, ADT+abiraterone+docetaxel, ADT+apalutamide, ADT+bicalutamide, ADT+darolutamide+docetaxel, ADT+enzalutamide, ADT+orteronel, and ADT+rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT+bicalutamide, nilutamide, flutamide, ADT+bicalutamide+palbociclib, and ADT+nilutamide. ADT+docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis. Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT+docetaxel SOC. Even so, ADT+docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3'3-diindolylmethane suppresses esophageal cancer tumorigenesis.

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3'3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

Nanomedicine strategies to counteract cancer stemness and chemoresistance.

Cancer stem-like cells (CSCs) identified by self-renewal ability and tumor-initiating potential are responsible for tumor recurrence and metastasis in many cancers. Conventional chemotherapy fails to eradicate CSCs that hold a state of dormancy and possess multi-drug resistance. Spurred by the progress of nanotechnology for drug delivery and biomedical applications, nanomedicine has been increasingly developed to tackle stemness-associated chemotherapeutic resistance for cancer therapy. This review focuses on advances in nanomedicine-mediated therapeutic strategies to overcome chemoresistance by specifically targeting CSCs, the combination of chemotherapeutics with chemopotentiators, and programmable controlled drug release. Perspectives from materials and formulations at the nano-scales are specifically surveyed. Future opportunities and challenges are also discussed.

Treatment methods for patients suffering from acute lymphoblastic leukemia (all) - a brief review

Introduction and purpose: Acute lymphoblastic leukemia is a medical condition with underlying abnormal proliferation of cells of the lymphoid system which are blocked at an early stage of differentiation. As a result of impaired lymphocyte maturation, the proliferation and accumulation of immature blastic cells, derived from tumor-transformed bone marrow precursor cells, develop in the bone marrow. The infiltration of the bone marrow by leukemic cells results in failure of normal hematopoiesis, with subsequent anemia, thrombocytopenia and neutropenia. Acute lymphoblastic leukemia is among the most aggressive proliferative diseases, and survival time is a few to several weeks without appropriate treatment.Materials and methods: The literature available on PubMed was reviewed using the words “acute lymphoblastic leukemia ”, “ALL”, “acute lymphoblastic leukemia treatment”.Summary: Acute lymphoblastic leukemia was managed with a chemotherapeutic drug combination for several years, with median overall survival of approximately 80% for all newly diagnosed cases. Patients with higher-risk relapses receive more intensive treatment, while patients with more favorable outcomes can avoid more toxic effects. Multicenter randomized controlled trials conducted by international collaborative efforts are helping to advance overall survival by exploring novel treatments. Hope for the future of leukemia therapy is defining the underlying molecular trails in the pathogenesis of the disease and clarifying host pharmacogenetic factors further. If successful, these efforts will allow the identification of new genes with candidate proteins for targeted therapies.

Natural products as drug candidates for breast cancer (Review).

Progression of early-stage breast cancer to advanced-stage metastatic disease represents a major cause of death in women. Long-term conventional and targeted therapy for breast cancer includes multi-drug combinations of cytotoxic chemotherapeutics and pathway-selective small molecule inhibitors. These treatment options are frequently associated with systemic toxicity, intrinsic/acquired therapy resistance and emergence of a drug-resistant cancer stem cell population. This stem cell population has a chemo-resistant, cancer-initiating, premalignant phenotype that is accompanied by cellular plasticity and metastatic potential. These limitations emphasize an unmet need to identify testable alternatives against therapy-resistant metastatic breast cancer. Natural products such as dietary phytochemicals, nutritional herbs and their constitutive bioactive agents have documented human consumption, and lack detectable systemic toxicity and resultant off-target unfavorable side effects. Because of these advantages, natural products may represent testable alternatives for therapy-resistant breast cancer. The present review discusses published evidence for growth inhibitory efficacy of natural products on cellular models for molecular subtypes of clinical breast cancer and development of drug-resistant stem cell models. Collectively, this evidence validates mechanism-based experimental approaches to screen and prioritize efficacious bioactive agents from natural products as novel drug candidates that may function as therapeutic alternatives for breast cancer.