Conventional Anticancer Therapies Research Articles

ROLE OF AYURVEDIC MEDICINES ON CARCINOMA GALL BLADDER AFTER CONVENTIONAL ANTI-CANCER THERAPY: A RANDOMISED CONTROL TRIAL

Gallbladder cancer (GBC) arises from the cystic duct and gallbladder lining, presenting as a thickening in the bile duct wall or a diffuse mass. Arbuda and Gulma are considered malignant tumours in Ayurveda. Acharya Charaka associates Gulma, a type of shotha, with the pittashaya (gall bladder) among the five adhishthans. Acharya Sushruta defines Gulma as "any granthi between hruday and Basti pradesh." Aim: To evaluate the efficacy of Ayurvedic medicine on associated signs and symptoms of carcinoma gall bladder following conventional anti-cancer therapy. Objective: To evaluate the QOL of the studied patient of carcinoma gall bladder following conventional anti-cancer therapy. Materials and methods: 20 patients suffering from the associated signs and symptoms of carcinoma gall bladder following conventional anti-cancer therapy were enrolled and randomly divided into two groups, i.e., Study Group B, Brihat Loknath Rasa 250 mg with lukewarm water, Mahashankh vati 250 mg with buttermilk, and Drakshavleha 6 gm with milk. In Control Group A, patients undergoing modern medicine were observed for 60 days. Results and Conclusion: The analysis of the relief percentage of the (Overall therapy) shows that the % relief for Study Group patients was 43.40% and the relief for Control Group was 38.68%. In conclusion, Ayurveda has the potential for symptomatic management of gallbladder cancer (GBC) by aligning with Pitta pradhan sannipatika Gulma. While a holistic approach and Ayurvedic principles show promise, more research in Ayurvedic oncology is required for validation.

Cell cycle heterogeneity and plasticity of colorectal cancer stem cells.

Cancer stem cells (CSCs) are a long-lived and self-renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5+ CSCs as well as quiescent Lgr5+ CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC.

A57 LONG-TERM EXPOSURE TO ANTICANCER TREATMENTS INCREASES AUTOPHAGY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background The most common type of esophageal cancer, esophageal squamous cell carcinoma (ESCC), has a 5-year survival rate of only 15%. This low survival rate is to some extent attributed to a high relapse rate, which is, in part, linked to the presence of cancer stem cells (CSC). CSC are a subpopulation of tumor cells that show reduced sensitivity to conventional anticancer therapies, increased potency and self-renewal capacities. With that in mind, ESCC cell lines were exposed in a prolonged manner to anticancer treatments (radiotherapy, 5-FU chemotherapy, and combined therapy) in our laboratory. As expected, an increase in the proportion of CSC (CD44highCD24high) was observed by flow cytometry following the treatments. In pursuit of innovative therapeutic approaches, we conducted an in-depth investigation of the proteomic profiles of these cell lines by mass spectrometry (MS), seeking to unveil novel biological mechanisms. Interestingly, many proteins associated with metabolism and autophagy were modulated. Several alterations were observed by a metabolomic approach as well, namely an increase in intracellular lactate concentration. Recently, a novel role for lactate has been described: lactylation, which is a post-translational modification. Lactylome of those cell lines revealed alteration in proteins related to autophagy and those results led to my research project. Aims Investigate the role of lactylation in autophagy of ESCC. Methods Human ESCC cell lines (including the cell lines exposed to anticancer treatments) will be used as cell culture models. Cell and organoid cultures, mass spectrometry, qPCR, WB, and proliferation assay were used. Results MS analysis of proteins related to autophagy (i.e. RAB1B, CK2, SNX6 et GABARAP) suggests differential regulation of autophagy in cell lines exposed to prolonged treatments. A strong contribution of the 5-FU treatment to the autophagic modification is observable in the double-treated cells. Thus, we confirmed an increase in the LC3BII/I ratio by WB in the cell lines exposed to anticancer treatments. LC3BII/I WB used in combination with Bafilomycin A1 treatment for inhibition of autophagosome and lysosome fusion is a commonly used read-out for autophagic flux. To further study the link between lactylation, autophagy and CSC, we screened 10 human ESCC cell lines for their LC3BII/I ratio. Four cell lines were selected: TE1, TE2, HCE4 and TE5. Using Bafilomycin A1, we confirmed that the autophagic flux in those cell lines was not blocked. Those cell lines will now be used to perform lactylome analysis of sorted CSC cells. Conclusions In brief, our results showed that the autophagic flux is increased in cells exposed to prolonged treatments. This suggests that autophagy could play a role in ESCC response to treatment. Funding Agencies CIHRTRIANGLE, Chaires de recherche du Canada, CRCHUS, Université de Sherbrooke

Association of Geriatric Nutritional Risk Index With Immune Checkpoint Inhibitor Treatment Duration and Adverse Events in Lung Cancer.

Compared to conventional cytotoxic anticancer agent-based therapy, treatment with immune checkpoint inhibitors (ICI) significantly prolongs overall survival. The Geriatric Nutritional Risk Index (GNRI) has been used as a new prognostic indicator in cancer. As nutritional status is associated with prognosis and indicates treatment response, we investigated the effect of the pretreatment GNRI on the (1) occurrence of ICI-induced immune-related adverse events (ir-AE) and (2) association with time to treatment failure (TTF) in ICI monotherapy for lung cancer. In this study, 127 patients with lung cancer who were treated with ICI monotherapy were retrospectively enrolled. Based on a cutoff value of 92 for the GNRI, we investigated intergroup differences in the occurrence of adverse events and their association with TTF in the High-GNRI (≥92) and Low-GNRI (<92) groups. For intergroup comparisons, we used the Student's t-test, Welch's t-test, Fisher's direct probability test, and Mann-Whitney's U-test, and factors with p<0.05 in the intergroup comparison were extracted as explanatory variables. Based on the pretreatment GNRI, the median TTF was 5.1 months (95%CI=2.4-7.9 months) in the High-GNRI group and 2.3 months (95%CI=1.6-3.1 months) in the Low-GNRI group, with the High-GNRI group having a significantly longer TTF (p<0.01). The incidence of skin rash (p=0.0129) and pruritus (p<0.01) was significantly higher in the High-GNRI group. Pretreatment GNRI influences the continuation of ICI monotherapy. The High-GNRI group demonstrated a significantly higher frequency of skin lesions, which may have influenced the prolongation of TTF.

In silico identification of potential protein kinase C alpha inhibitors from phytochemicals from IMPPAT database for anticancer therapeutics: a virtual screening approach

Protein Kinase C alpha (PKCα) is a critical signaling molecule that plays a crucial role in various physiological processes, including cell growth, differentiation, and survival. Over the years, there has been a growing interest in targeting PKCα as a promising drug target for the treatment of various diseases, including cancer. Targeting PKCα can, therefore, serve as a potential strategy to prevent cancer progression and enhance the efficacy of conventional anticancer therapies. We conducted a systematic search for promising compounds for their anticancer potential that target PKCα using natural compounds from the IMPPAT database. The initial compounds were screened through various tests, including analysis of their physical and chemical properties, PAINS filter, ADMET analysis, PASS analysis, and specific interaction analysis. We selected those that showed high binding affinity and specificity to PKCα from the screened compounds, and we further analyzed them using molecular dynamics simulations (MDS) and principal component analysis (PCA). Various systematic parameters from the MDS analyses suggested that the protein–ligand complexes were stabilized throughout the simulation trajectories of 100 nanoseconds (ns). Our findings indicated that compounds Nicandrenone and Withaphysalin D bind to PKCα with high stability and affinity, making them potential candidates for further research in cancer therapeutics innovation in clinical contexts. Communicated by Ramaswamy H. Sarma

Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy.

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed.

Frenemies in the Microenvironment: Harnessing Mast Cells for Cancer Immunotherapy.

Tumor development, progression, and resistance to therapies are influenced by the interactions between tumor cells and the surrounding microenvironment, comprising fibroblasts, immune cells, and extracellular matrix proteins. In this context, mast cells (MCs) have recently emerged as important players. Yet, their role is still controversial, as MCs can exert pro- or anti-tumor functions in different tumor types depending on their location within or around the tumor mass and their interaction with other components of the tumor microenvironment. In this review, we describe the main aspects of MC biology and the different contribution of MCs in promoting or inhibiting cancer growth. We then discuss possible therapeutic strategies aimed at targeting MCs for cancer immunotherapy, which include: (1) targeting c-Kit signaling; (2) stabilizing MC degranulation; (3) triggering activating/inhibiting receptors; (4) modulating MC recruitment; (5) harnessing MC mediators; (6) adoptive transferring of MCs. Such strategies should aim to either restrain or sustain MC activity according to specific contexts. Further investigation would allow us to better dissect the multifaceted roles of MCs in cancer and tailor novel approaches for an "MC-guided" personalized medicine to be used in combination with conventional anti-cancer therapies.

Human embryonic stem cells exert antitumor effects on prostate cancer cells in a co-culture microenvironment.

Prostate cancer is currently the most common malignancy among men. Given the limitations of current conventional anticancer therapies, new high-risk treatments are urgently needed. Previous studies have shown that embryonic stem cells (ESCs) can reverse the tumorigenic phenotype of tumor cells. However, there are still challenges in using human ESCs (hESCs) directly in cancer treatment. To facilitate the practical application of hESCs, we established a co-culture system consisting of prostate cancer cell lines and hESCs and investigated the antitumor activity of the supernatant of the co-culture system (Co-Sp) in vitro and in vivo, as well as the underlying mechanisms involved. The Co-Sp decreased the viability of prostate cancer cells in a concentration-dependent manner, significantly inhibited colony formation, and induced cell cycle arrest at the G0/G1 phase of the cell cycle. In addition, Co-Sp promoted apoptosis of prostate cancer cells and inhibited cell migration and invasion. In vivo studies also revealed that Co-Sp inhibited tumor growth in the xenograft model. Mechanistic studies showed that Co-Sp reduced the expression of cyclin D1, cyclin E, CDK4, CDK2, MMP-9, MMP-1, and Bcl-2, and increased the expression of p21, cleaved caspase-9, cleaved caspase-3, cleaved PARP, and Bax in prostate cancer cells. Furthermore, the Co-Sp decreased the phosphorylation of PI3K, AKT, and mTOR in cells and tumor tissues. Taken together, our results indicated that the Co-Sp has potent antitumor activity and could directly inhibit tumor growth. Our findings provide a new and effective way for the application of hESCs in cancer therapy and contribute to a new strategy for clinical stem cell therapy.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Mesenchymal stem cells- an excellent therapeutic agent for cancer.

Despite rapid advancement in research of diagnostics and therapeutics, cancer is the most dangerous disease-causing millions of deaths worldwide. Many of the conventional anticancer therapies can even lead to developing resistance to therapy and recurrence of cancer. To find a new, alternative treatment strategy for a variety of ailments scientists and researchers have turned their attention to cell therapies and regenerative medicine. Stem cells are now being researched for their extensive potential application in therapy for several incurable illnesses including cancer. One of the most often employed cell types for regenerative medicine is mesenchymal stem cells. Mesenchymal stem cells (MSCs) are considered a promising source of stem cells in personalized cell-based therapies. The inherent tumor tropic and immune-modulatory properties of MSCs can be used to target cancer cells. This review aims to focus on the anticancer properties of MSCs and their effect on different signaling pathways. Later on, we discuss the advantages of engineered MSCs over non-engineered MSCsin cancer therapy.

Exploring the anti-cancer potential of dietary phytochemicals for the patients with breast cancer: A comprehensive review.

The most common and deadly cancer in female is breast cancer (BC) and new incidence and deaths related to this cancer are rising. Several issues, that is, high cost, toxicity, allergic reactions, less efficacy, multidrug resistance, and the economic cost of conventional anti-cancer therapies, has prompted scientists to discover innovative approaches and new chemo-preventive agents. Numerous studies are being conducted on plant-based and dietary phytochemicals to discover new-fangled and more advanced therapeutic approaches for BC management. We have identified that natural compounds modulated many molecular mechanisms and cellular phenomena, including apoptosis, cell cycle progression, cell proliferation, angiogenesis and metastasis, up-regulation of tumor-suppressive genes, and down-regulation of oncogenes, modulation of hypoxia, mammosphere formation, onco-inflammation, enzymatic regulation, and epigenetic modifications in BC. We found that a number of signaling networks and their components such as PI3K/Akt/mTOR, MMP-2 and 9, Wnt/-catenin, PARP, MAPK, NF-κB, Caspase-3/8/9, Bax, Bcl2, Smad4, Notch1, STAT3, Nrf2, and ROS signaling can be regulated in cancer cells by phytochemicals. They induce up-regulation of tumor inhibitor microRNAs, which have been highlighted as a key player for ani-BC treatments followed by phytochemical supplementation. Therefore, this collection offers a sound foundation for further investigation into phytochemicals as a potential route for the development of anti-cancer drugs in treating patients with BC.

Experimental design of D-α-tocopherol polyethylene glycol 1000 succinate stabilized bile salt based Nano-vesicles for improved cytotoxicity and bioavailability of colchicine binding site inhibitor Candidates: In Vitro, in silico, and pharmacokinetic studies

Nowadays, conventional anticancer therapy suffers many pitfalls, including drastic side effects and limited therapeutic efficacy resulting from diminished oral bioavailability. So, in an attempt to enhance their poor solubility and oral bioavailability along with the cytotoxic activity, the developed lead compounds (C1 and C2) were loaded in D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified vesicles adopting thin film hydration technique. The formulations of the aforementioned candidates (F1 and F2, respectively) were elected as the optimum formula with desirability values of 0.701 and 0.618, respectively. Furthermore, an outstanding enhancement in the drug's cytotoxic activity against different cancer cell lines (MCF-7, HepG-2, MDA-MB-321, A375, and MGC-803) after being included in the nano-TPGS-modified optimum formula was noticed relative to the unformulated compounds. The formula F1 showed the best cytotoxic activities against HepG-2 with an IC50 = 3 µM. Furthermore, regarding MCF-7, F1 was shown to be the most potent and protective among all the tested formulations with an IC50 = 6 µM. Besides, F1 exerted the best caspase 3/7 activity stimulation (around a 5-folds increase) compared to control in the MCF-7 cell line. Notably, it was disclosedthat both C1 and C2 induced cell cycle arrest at the resting S growth phase. Moreover, C1 and C2 decreased tubulin concentrations by approximately 2-folds and 6-folds, respectively. Meanwhile, the conducted molecular docking studies ensure the eligible binding affinities of the assessed compounds. Besides, MD simulations were performed for 1000 ns to confirm the docking results and study the exact behavior of the target candidates (C1 and C2) toward the CBS.

Nanomedicines: intervention in inflammatory pathways of cancer.

Inflammation is a complex defense process that maintains tissue homeostasis. However, this complex cascade, if lasts long, may contribute to pathogenesis of several diseases. Chronic inflammation has been exhaustively studied in the last few decades, for its contribution in development and progression of cancer. The intrinsic limitations of conventional anti-inflammatory and anti-cancer therapies triggered the development of nanomedicines for more effective and safer therapies. Targeting inflammation and tumor cells by nanoparticles, encapsulated with active therapeutic agents, offers a promising outcome with patient survival. Considerable technological success has been achieved in this field through exploitation of tumor microenvironment, and recognition of molecules overexpressed on endothelial cells or macrophages, through enhanced vascular permeability, or by rendering biomimetic approach to nanoparticles. This review focusses on the inflammatory pathways in progression of a tumor, and advancement in nanotechnologies targeting these pathways. We also aim to identify the gaps that hinder the successful clinical translation of nanotherapeutics with further clinical studies that will allow oncologist to precisely identify the patients who may be benefited from nanotherapy at time when promotion or progression of tumor initiates. It is postulated that the nanomedicines, in near future, will shift the paradigm of cancer treatment and improve patient survival.

Abstract CT169: Bioplatin (NTPX-07) as an oral nano platinum in patients of advanced stage malignancy: Outcomes of a phase I clinical trial

Abstract Purpose: Platinum derivatives are widely used for treating a variety of solid tumours. Besides its direct cytotoxic action, Platinum derivatives play an important role in antitumor immune response, mainly by its inherent capacity to induce immunogenic cell death. Induction of apoptosis using novel therapeutics can be considered a key therapeutic strategy for preventing recurrence and metastasis in cancer patients. Bioplatin is an oral, nano platinum-based compound manufactured using patented innovative processing, based on green technology with an aim of retaining its anti-cancer properties while at the same time reducing its dose limiting toxicities. This compound has demonstrated the property of inducing apoptosis in cancer cells by preventing DNA replication. Since Bioplatin is developed with an aim of arresting disease progression and improving progression-free survival/disease-free survival its administration is expected to be for a longer duration hence its oral dosing and good tolerability are of utmost importance. Methods: The present study, Phase-I multicentric clinical trial (CTRI/2017/06/008778) was conducted. with an aim of determining the maximum tolerated dose, safety, tolerability and effect on Quality-of-life (QoL) Bioplatin was administered orally for 21 consecutive days to advanced-stage cancer patients of solid tumours who were not responding to any conventional anticancer therapy. Dose escalation was carried out to determine the Maximum Tolerated Dose (MTD). Results: A total of 14 patients received Bioplatin at 4 dose levels, 10 mg, 20 mg, 40 mg, and 60 mg Cohort. The mean progression-free survival (PFS) was 40.25 ± 13.47 days. The highest mean PFS of 50.67 ± 6.66 days was observed in the 40 mg Cohort. The mean PFS was 37.67 ± 16.74 days in 60 mg cohort. Analysis of QoLusing FACT-G showed improvement in QoL (FACT-G) in the 60 mg cohort as compared to Day 1 (p&amp;lt;0.05). No dose-limiting toxicity was reported. Conclusion: Considering that Bioplatin can be administered orally, its tolerability, and its property to delay tumor growth, we propose that it can be used for the treatment of patients with platinum-sensitive tumours. Bioplatin has the potential as an orally consumable immunotherapy agent for longer duration. It is expected to increase disease-free survival (DFS) post-surgery/chemotherapy or as maintenance therapy with other agents in advanced stages patients of platinum-sensitive tumours for improving Quality of life and increasing survival. The findings of the study warrant further clinical evaluation. Citation Format: Yogesh Bendale, Vikram Gota, Rajnish Nagarkar, Eeshani Bendale, Nandinee Khot, Surendra Nagre, Avinash Kadam. Bioplatin (NTPX-07) as an oral nano platinum in patients of advanced stage malignancy: Outcomes of a phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT169.

Role of epigenetic drugs in sensitizing cancers to anticancer therapies: emerging trends and clinical advancements.

Epigenetic changes play a significant role in cancer progression, maintenanceand therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.

Biomaterial-based platforms for modulating immune components against cancer and cancer stem cells.

Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells.

Photodynamic therapy with zinc phthalocyanine enhances the anti-cancer effect of tamoxifen in breast cancer cell line: Promising combination treatment against triple-negative breast cancer?

Photodynamic therapy (PDT) is a light-based anti-neoplastic therapeutic approach. Growing evidence indicates that combining conventional anti-cancer therapies with PDT can be a promising approach to treat malignancies. Herein, we aimed to investigate anti-cancer effects of the combination treatment of zinc phthalocyanine (ZnPc)-PDT with tamoxifen (TA) on MDA-MB-231 cells (as a triple-negative breast cancer (TNBC) cell line). For this purpose, we investigated the cytotoxicity of TA and ZnPc-PDT on MDA-MB-231 cells performing the MTT assay. The effect of TA and ZnPc-PDT on the apoptosis of MDA-MB-231 cells was studied using Annexin V/PI and DAPI staining. The wound-healing assay, and colony formation assay were performed to study the effect of TA and ZnPc-PDT on the migration, and clonogenicity of MDA-MB-231 cells, respectively. The qRT-PCR was done to study the gene expression of caspase-8, caspase-9, caspase-3, ZEB1, ROCK1, SNAIL1, CD133, CD44, SOX2, and ABCG2 (ATP-binding cassette sub-family G member 2). Based on our results, monotherapies with TA and ZnPc-PDT can remarkably increase cell cytotoxicity effects, stimulate apoptosis via downregulating Bcl-2 and upregulating caspase-3 and caspase-9, inhibit migration via downregulating SNAIL1 and ZEB1, and suppress clonogenicity via downregulating SOX2 and CD44 in MDA-MB-231 cells. Besides, these monotherapies can downregulate the expression of ABCG2 in MDA-MB-231 cells. Nevertheless, the combination treatment can potentiate the above-mentioned anti-cancer effects compared to monotherapy with TA. Of interest, the combined treatment of TA with ZnPc-PDT can synergically increase cell cytotoxicity effects on MDA-MB-231 cells. In fact, synergistic effects were estimated by calculation of Combination Index (CI); that synergistic outcomes were observed in all groups. Also, this combination treatment can significantly upregulate the caspase-8 gene expression and downregulate ROCK1 and CD133 gene expression in MDA-MB-231 cells. Overall, our results show that ZnPc-PDT can more sensitize the MDA-MB-231 cells to TA treatment. Based on our knowledge and experiment, the synergistic effects of ZnPc-PDT and TA deserve further evaluation in cancer research.

Recent advances in oridonin derivatives with anticancer activity.

Cancer is a leading cause of mortality responsible for an estimated 10 million deaths worldwide in 2020, and its incidence has been rapidly growing over the last decades. Population growth and aging, as well as high systemic toxicity and chemoresistance associated with conventional anticancer therapies reflect these high levels of incidence and mortality. Thus, efforts have been made to search for novel anticancer drugs with fewer side effects and greater therapeutic effectiveness. Nature continues to be the main source of biologically active lead compounds, and diterpenoids are considered one of the most important families since many have been reported to possess anticancer properties. Oridonin is an ent-kaurane tetracyclic diterpenoid isolated from Rabdosia rubescens and has been a target of extensive research over the last few years. It displays a broad range of biological effects including neuroprotective, anti-inflammatory, and anticancer activity against a variety of tumor cells. Several structural modifications on the oridonin and biological evaluation of its derivatives have been performed, creating a library of compounds with improved pharmacological activities. This mini-review aims to highlight the recent advances in oridonin derivatives as potential anticancer drugs, while succinctly exploring their proposed mechanisms of action. To wind up, future research perspectives in this field are also disclosed.

A reliable mouse model of liver and lung metastasis by injecting esophageal cancer stem cells (CSCs) through tail-vein injection.

Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive tumor with increased metastatic potential. Recent evidence suggests that esophageal CSCs have a crucial role in tumor initiation, progression, and resistance to conventional anti-cancer therapies. The study aimed to develop mouse model to mimic the late steps of the metastasis process using a tail-vein injection of esophageal CSCs. The sphere formation assay was used to enrich CSCs. For analysis of tumorigenicity, YM-1 adherent cells and enriched CSCs were injected subcutaneously into dorsal flank of nude mice. The expression of SLUG, E-cad, and CTHRC1 genes was examined by Real-Time qRT-PCR and immunohistochemistry (IHC) methods. To assess the metastatic potential of adherent YM-1 cells and their enriched CSCs, we injected the cells into the tail vein of nude mice. Our findings showed the up-regulation of SLUG and down-regulation of E-cad in the esophageal CSC-derived tumors (ECSCTs) compared to adherent cells-derived tumors. There was no statistically significant difference between CTHRC1 gene expressions in both groups of tumors. IHC staining confirmed the higher expression of SLUG protein in ECSCTs compared to adherent cell-derived tumors. Enriched CSCs were able to metastasize to the lungs and livers after three months, but, metastasis of adherent cells wasn't observed. Our study showed esophageal CSCs injected through the tail-vein injection can migrate and metastasize to the lung and liver after three months. The developed metastatic mouse model can be a valuable and relevant model to investigate the molecular and cellular mechanisms of metastasis and develop successful targeted therapies against ESCC. The present study is one of the few studies that investigate the metastasis of esophageal cancer stem cells (ESCC type) through injection into the tail vein of nude mice.

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

Primary malignant brain tumors are the most common solid neoplasm in childhood. Despite recent advances, many children affected by aggressive or metastatic brain tumors still present poor prognosis, therefore the development of more effective therapies is urgent. Cancer stem cells (CSCs) have been discovered and isolated in both pediatric and adult patients with brain tumors (e.g., medulloblastoma, gliomas and ependymoma). CSCs are a small clonal population of cancer cells responsible for brain tumor initiation, maintenance and progression, displaying resistance to conventional anticancer therapies. CSCs are characterized by a specific repertoire of surface markers and intracellular specific pathways. These unique features of CSCs biology offer the opportunity to build therapeutic approaches to specifically target these cells in the complex tumor bulk. Treatment of pediatric brain tumors with classical chemotherapeutic regimen poses challenges both for tumor location and for the presence of the blood-brain barrier (BBB). Lastly, the application of chemotherapy to a developing brain is followed by long-term sequelae, especially on cognitive abilities. Novel avenues are emerging in the therapeutic panorama taking advantage of nanomedicine. In this review we will summarize nanoparticle-based approaches and the efficacy that NPs have intrinsically demonstrated and how they are also decorated by biomolecules. Furthermore, we propose novel cargoes together with recent advances in nanoparticle design/synthesis with the final aim to specifically target the insidious CSCs population in the tumor bulk.