Cancer Chemotherapy Agents Research Articles

Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine.

The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.

<i>In silico</i> Pharmacokinetic, Molecular Docking and Molecular Dynamics Simulation Studies of Phytochemicals isolated from <i>Cascabela thevetia</i> as Potential Anticancer Agents

Cascabela thevetia generally recognized as yellow oleander, Lippold or lucky nut (in English) and Peeli Kaner (in Hindi), is Indigenous to Central America and Mexico and widely distributed in the Indian subcontinent as well, is a medicinally important herb that has long been employed to treat disorders like ulcers, scabies, haemorrhoids, and tumour dissolution. Seven Cardenolides (Compounds 1-7) isolated from fruits of Cascabela thevetia are selected as ligands for in silico pharmacokinetic (ADME properties) and drug-likeness studies via the Swiss ADME online server. Further, molecular docking studies were accomplished for the selected ligands via the Auto Dock Vina module of PyRx to explore the receptor-ligand interaction with β-tubulin (a potential target for anticancer drugs, PDB ID: 1SA0), to find out potential therapeutic ligands for cancer chemotherapy. From the studies performed it was found that most of the ligands (compounds) have the capability of good binding affinity with the receptor, β-tubulin, good drug-likeness and ADME properties among which compounds 3, 6 and 7 are the best drug candidates because they followed the Lipinski rule of 5 with 0 violation and also have good binding affinities (-8.3, -8.0 and -7.9 kcal/mol respectively) against the target protein. Hence, compounds 3, 6 and 7 can be developed as novel therapeutic agents in cancer chemotherapy. Further, a Molecular Dynamics (MD) simulation study of best-docked ligand 3 was performed to establish its stability and validate molecular docking results. Based on simulation results, it may be stated that ligand 3 was firmly attached to the receptor protein during MD simulation since none of the conformations of the receptor-ligand complex were unstable, and no folding or unfolding of the complex took place. Therefore, compound 3 can be considered a good inhibitor of β-tubulin after validation of various parameters of drug discovery.

Sendai virus-mediated RNA delivery restores fertility to congenital and chemotherapy-induced infertile female mice.

Current infertility treatment strategies focus on mature gametes, leaving a significant proportion of cases with gamete progenitors that stopped complete differentiation. On the other hand, recent advancements in next-generation sequencing have identified many candidate genes that may promote maturation of germ cells. Although gene therapy has shown success in mice, concerns about the integration of DNA vectors into oocytes hinder clinical applications. Here, we present the restoration of fertility in female mice through Sendai virus (SeV)-mediated RNA delivery. Ovaries lacking Kitl expression exhibit only primordial follicles due to impaired signaling to oocytes expressing the KIT tyrosine kinase. Despite SeVs being immunogenic and larger than the blood-follicle barrier, the administration of Kitl-expressing SeVs reinitiated oogenesis in genetically infertile mice that have only primordial follicles, resulting in the birth of normal offspring through natural mating. This virus also effectively addressed iatrogenic infertility induced by busulfan, a widely used cancer chemotherapy agent. Offspring born through SeV administration and natural mating displayed normal genomic imprinting patterns and fertility. Since SeVs pose no genotoxicity risk, the successful restoration of fertility by SeVs represents a promising approach for treating congenital infertility with somatic cell defects and protecting fertility of cancer patients who may become infertile due to loss of oocytes during cancer therapy.

Decorating Delivery Vehicles Using Hyaluronic Acid Oligosaccharides Enables Active Targeting Toward Cancer and Minimizes Adverse Effect of Chemotherapeutics.

The major drawback of conventional chemotherapeutic treatment is the non-specificity or inability to ascertain and target cancerous cells directly. In this study, an active targeting strategy that is poised to carry the anticancer agents to the desired sites for therapeutic action while avoiding toxicity to normal organs is provided. The active targeting of delivery vehicles is achieved by ligand-receptor interactions, in particular the specific binding between hyaluronic acid oligosaccharides (oHAs) and CD44 receptors. This study first prepares oHAs by the size-exclusion chromatography and utilizes them to decorate chitosan (CTS) as basic materials (oHAs-CTS) for drug delivery, then fabricates oHAs-CTS into micro/nanoscale carriers to encapsulate agents for cancer chemotherapy. The oHAs-CTS micro/nanocarriers exhibit high drug encapsulation efficiency (58-87%), and the drug releases present a sustained behavior. Notably, oHAs-CTS delivery vehicles display an enhanced active targeting toward cancers and alleviate the cytotoxic effects on normal cells. Additionally, in vivo results show that drug-laden oHAs-CTS nanocarriers demonstrate a significant inhibitory effect on 4 T1 tumors without any toxicity to the major organs. Taken together, the findings highlight the potential of oHAs-CTS micro/nanospheres as delivery vehicles with enhanced active targeted capability toward cancers and minimized adverse effects of chemotherapeutic agents for cancer treatment.

Fibroin nanodisruptor with Ferroptosis-Autophagy synergism is potent for lung cancer treatment

Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.

Apoptotic Potential and Molecular Docking of 3,4-Dihydro-lactucin, a Compound With Anticancer Properties Derived from Microbispora rosea AL22.

Tetrazolium-based cell proliferation assays using MDA-MB-231 and HeLa cells revealed that 3,4-dihydro-lactucin (3,4-DHL), a compound isolated from Microbispora rosea AL22, possesses anticancer properties. Apoptotic cell death was observed in 3,4-DHL-treated cells. Lactucopicrin, a related compound, reportedly exerts anticancer activity against different cancer types. However, data on the anticancer mechanism of lactucins are limited. This study aimed to investigate apoptosis induction in MDA-MB-231 cells treated with 3,4-DHL. Morphological changes, changes in mitochondrial membrane potential, and apoptosis induction in MDA-MB-231 cells treated with 3,4-DHL were investigated. Furthermore, molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of anti-apoptotic proteins were performed to determine the effector mechanism of 3,4-DHL. 3,4-DHL induced cytotoxicity at a half-maximal inhibitory concentration of 37.62 μg/ml, along with various morphological alterations in apoptotic and viable cells. Furthermore, 3,4-DHL-treated cells showed mitochondrial membrane potential depolarization, intense annexin V-fluorescein isothiocyanate staining, and increased caspase 3 and 8 activities. Molecular-docking studies demonstrated that 3,4-DHL should bind to the active site of various anti-apoptotic proteins, forming stable complexes. Our findings revealed that 3,4-DHL has great potential to be used as an apoptosis-inducing agent in cancer therapy. However, further in-vivo confirmation is required in evaluation of 3,4-DHL as an anticancer agent in cancer chemotherapy.

Green synthesis, in silico modeling, and biological evaluation of N-substituted (Z)-5-arylidene imidazolidine/thiazolidine-2,4-dione/4-thione derivatives catalyzed by Bu SO3H core-shell nanostructures.

In this effort, the immobilization of guanidine-sulfonate on the surface of Fe3O4 MNPs (magnetic nanoparticles) as a novel acid nanocatalyst has been successfully reported for the synthesis of N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and related cyclic derivatives, including rhodanine (RHD) and hydantoin (HYD) via a one-pot multiple-component reaction under green conditions. The products were characterized by SEM, TEM, TGA, EDS, BET techniques, VSM, and FTIR. The novel compounds synthesized using this methodology, designated as series La (1-9), Lb (1-8), and Lc (1-8), were subjected to anticancer screening against A549 and MCF7cell lines via MTT assays. Notably, several compounds (L1a, L2a, L3a, L1b, L2b, L3b, and L4b) exhibited potent antiproliferative activities, with observed IC50 values as low as 1.23 μM and 1.02 μM against MCF-7 cells, thereby outperforming the established anticancer drugs doxorubicin and cisplatin. Molecular docking and dynamics simulations revealed that ligands L1a, L2a, and L3a strongly interact with the protein target 3CD8, with L1a displaying significant hydrophobic and hydrogen bonding interactions and L2a engaging in unique pi-pi stacking with key residues. For protein 2WGJ, ligand L4b exhibited exceptional binding affinity, characterized by robust hydrogen bonding, hydrophobic interactions, and additional stabilizing mechanisms such as water bridges and pi interactions. Hence, N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and its cyclic derivatives may serve as promising candidates for further exploration in the development of new multi-target cancer chemotherapy agents. These findings introduce promising anticancer agents and establish Fe3O4 MNPs as a versatile and environmentally sustainable catalytic platform in drug discovery.

Cutaneous adverse effects of chemotherapy in cancer patients: A clinico epidemiological study

With chemotherapy being the major modality of treatment, cutaneous and systemic side effects have been a concern for not only the patients, but also the treating clinicians. Because chemotherapy target not only the cancer cells, but also the other rapidly proliferating cells, skin and skin appendages like hair and nails are most commonly affected.: To study the cutaneous adverse events associated with the commonly used cancer chemotherapy drugs.: 120 patients of clinically diagnosed cancer who underwent chemotherapy and satisfied the inclusion and exclusion criteria were included in this observational study. Photographic images of skin, hair and nails were taken before and after every cycle of chemotherapy were collected. Data were analysed using SPSS version 16.0.: 120 patients including 72 females and 48 males were included in this study with majority (56%) belonging to age group of 55-70 years. The common indications for chemotherapy were carcinoma breast (34%), carcinoma oropharynx (22%) and carcinoma stomach (12%).Hair changes were the most common presentation, reported in 38 patients, skin changes in 35 cases, nail changes in 15 cases. Xerosis (46%) and hyperpigmentation (22%) were the most commonly observed adverse event affecting skin.: Since all cancer chemotherapy agents are not target based, adverse effects of skin and appendages become inevitable. However, early detection of such adverse effects can help them managed effectively and thereby reducing the morbidity and increasing the quality of life of cancer patients.

BI21 The development of diffuse extragenital lichen sclerosus in a patient on palbociclib and fulvestrant for metastatic breast cancer

Abstract A 59-year-old woman with skin phototype VI was commenced on palbociclib (cyclin-dependent kinase 4/6 inhibitor) and fulvestrant (oestrogen receptor antagonist) as chemotherapy agents for metastatic breast cancer. Two months later, she developed a new widespread rash. Past medical history included atopic dermatitis but no autoimmune conditions. Denosumab was her only other medication. On examination, she had hyperpigmented thickened plaques with purple hue and sclerotic plaques with cigarette wrinkling on her buttocks, arms, neck, abdomen and axillae. She also had widespread hypopigmentation. Biopsies showed hyperkeratosis and a lichenoid inflammatory reaction with pigmentary incontinence. Clinicopathological correlation supported the diagnosis of extragenital lichen sclerosus (EGLS). Palbociclib and fulvestrant were stopped and she noted improvement of her rash within 3 weeks. She was also managed with potent topical steroids, which eased her symptoms and further improved the appearance. Lichen sclerosus (LS) is a chronic inflammatory condition affecting the anogenital area. EGLS occurs in approximately 15–20% of those with LS, and only 6% of patients with EGLS do not have genital involvement at diagnosis. LS and EGLS are characterized by white papules, sclerosus and erosions with atrophic plaques. In the skin of colour, the presentation is varied, with hypo- or hyperpigmentation. Currently, the pathogenesis of EGLS is poorly understood, with studies suggesting an autoimmune aetiology, with possible genetic, infectious, hormonal, trauma and drug associations. In addition to specific autoantibodies, the absence of a suppressive function of regulatory T cells may contribute to the induction of autoimmunity. A recent association with immune checkpoint inhibitors (ICIs) further establishes this link. There are 12 case reports of ICIs and LS/EGLS, but cell cycle inhibitors associated with EGLS have not yet been reported (Silvestri M, Cristaudo A, Morrone A et al. Emerging skin toxicities in patients with breast cancer treated with new cyclin-dependent kinase 4/6 inhibitors: a systematic review. Drug Saf 2021; 44:725–32). Laboratory studies demonstrate increased T-cell activation with abemaciclib, a cell cycle inhibitor, which has been hypothesized to have other autoimmune drug associations (Truong K, Jones-Caballero M, Chou S et al. Lichen sclerosus and immune checkpoint inhibitors: a case and review of the literature. Australas J Dermatol 2023; 64:158–61). Other possible theories contributing to the development of EGLS include the Koebner effect of deep intramuscular injection of fulvestrant or subsequent low-oestrogen state. To the best of our knowledge, this is the first case of EGLS following these chemotherapy agents. This case hypothesizes the role of cell cycle inhibitors contributing to the aetiology in a mechanism similar to that of ICIs. It also demonstrates the difference in presentation of EGLS in skin of colour.

A study of antibody conjugates for the treatment of inflammatory breast cancer.

e15016 Background: Inflammatory breast cancer (inflammatory carcinoma) is a rare metastatic malignant tumor, it accounts for about 2% of all breast cancer cases. Despite its low incidence, inflammatory breast cancer is highly invasive, its five-year survival rate is less than 41%, making its prognosis the worst of all breast cancer subtypes, and effective drugs are urgently needed in clinical practice. Therefore, our study develops novel antibody conjugate drugs that can target overexpressed-ICAM-1 in inflammatory breast cancer cells as an original molecular target precisely. Methods: In this study, flow cytometry was used to perform precise and quantitative target screening of inflammatory breast cancer cell lines (SUM-149, KPL4), the endocytosis efficiency of ADC drugs was verified by flow cytometry efficiency analysis and single-photon confocal analysis, and the cytotoxicity of different drugs and cell lines was explored by CCK8 experiment. A nude mouse model of orthotopic xenograft inflammatory breast cancer was constructed, and the in vivo therapeutic effect of inflammatory breast cancer was observed by intravenous injection of two ICAM-1 antibody conjugates (ICAM-1-MMAE and ICAM-1-DXD), also the ADC drug structure with the best therapeutic effect for inflammatory breast cancer was screened. Results: ICAM-1 molecule in a variety of inflammatory breast cancer cell lines were highly over-expressed, and the antibody internalization rate was 51% at 4h, and after the peak the endocytosis efficiency slowed down into the plateau stage; ICAM1-MMAE and ICAM1-DXD are safer than first-line chemotherapy agents for breast cancer; The tumor volume was significantly reduced after administration into the orthotopic breast cancer xenograft model, which further verified the obvious effect of ADC drugs in vivo. Conclusions: Both ICAM-1-MMAE and ICAM-1-DXD have shown significant anti-inflammatory breast cancer effects in vitro and in vivo, and this study provides potential antibody conjugate drugs for targeted therapy of inflammatory breast cancer, which is expected to help improve the poor prognosis of inflammatory breast cancer.

Private Payer-Negotiated Rates for FDA-Approved Head and Neck Cancer Immunotherapy and Chemotherapy Agents.

To quantify the price that private payers pay hospitals for head and neck squamous cell carcinoma (HNSCC) treatments and identify hospital-level factors associated with price variation. Cross-sectional study. Price transparency files. Files from the top 50 hospitals in otolaryngology according to the US News and World Report were analyzed between December 2021 and June 2022. This study analyzed the following Food and Drug Administration-approved HNSCC therapies: pembrolizumab, nivolumab, cetuximab, cisplatin, carboplatin, and paclitaxel. Twenty-four (48%) hospitals reported prices for at least 1 medication in our sample. Newer biologics were significantly more expensive than traditional chemotherapeutic agents. Given approved medication regimens, all biologics in our sample have similar annual costs. Price markups over acquisition costs ranged between 109% (pembrolizumab, nivolumab) and 530% for carboplatin. Across hospitals, prices varied the most for paclitaxel, the cheapest medication in our sample, and prices varied the least for pembrolizumab the most expensive medication in our sample. Hospital 340B status and geographic location in the northeast/west are associated with lower price markups. Price nondisclosure remains a significant problem among hospitals. Newer biological medications are more expensive when compared to traditional chemotherapeutic agents. Prices vary significantly across hospitals, with lower price markups observed in 340B hospitals as well as hospitals located in the geographic northeast and west. It remains to be seen if price transparency will lead to more uniform pricing or lower costs of treatments.

The protective effect of taurine, piracetam and vinpocetine on etoposide-induced inflammation and brain injury in the serum of female albino rats.

Etoposide (ETP) is one of the leading antitumour agents in cancer chemotherapy. Many studies have reported on ETP-induced peripheral neuropathy; however, few reports have focused on its brain toxicity. The current research investigates the protective potential of taurine, piracetam and vinpocetine on serum biomarkers associated with inflammation and brain injury induced by ETP in a rodent model. A total of 30 female albino rats were equally divided into five groups; the 1st and 2nd groups were the control and ETP-treated groups, respectively, while the 3rd, 4th and 5th groups were ETP-treated rats cotreated with taurine, piracetam and vinpocetine, respectively. Administration of ETP reduced body weight significantly, enhanced production of serum proinflammatory cytokines including tumour necrosis factor-alpha, interleukin-1 beta (IL-1β) and IL-6 and decreased glutathione serum levels. Moreover, ETP treatment resulted in upregulation of glial fibrillary acidic protein expression and histopathological alterations in the rats' brain compared to the control group. Co-treatment with taurine, piracetam and vinpocetine counteracted ETP-induced brain injury and altered serum biomarkers levels. We concluded that co-treatment with vinpocetine could serve as a complementary therapeutic agent in reducing brain injury and toxicity induced by ETP.

Rapid Reduction of CEA and Stable Metastasis in an NRAS-mutant Rectal-Cancer Patient Treated With FOLFIRI and Bevacizumab Combined With Oral Recombinant Methioninase and a Low-Methionine Diet Upon Metastatic Recurrence After FOLFIRI and Bevacizumab Treatment Alone.

The choice of chemotherapy agents for RAS-mutant colorectal cancer is limited, and prognosis is poor compared to RAS-wild-type colorectal cancer. The purpose of the present study was to evaluate the effectiveness of methionine restriction combined with chemotherapy in a patient with NRAS-mutant rectal cancer. A 59-year-old female was diagnosed with lung-metastatic recurrence of NRAS-mutant rectal cancer two and a half years after resection of the primary tumor. She started chemotherapy, which consisted of fluorouracil, irinotecan (FOLFIRI), and bevacizumab, in October 2020. Eight months later, stereotactic body radiation therapy (SBRT) was performed to treat the lung metastases. She stopped chemotherapy at this point and had blood tests and computed tomography (CT) scans regularly. Her CEA level increased to 139.91 ng/ml and her lung metastasis became larger by September 2022. Therefore, she was reintroduced to FOLFIRI and bevacizumab in October 2022, and also started a low-methionine diet and oral recombinant methioninase (o-rMETase) as a supplement. After starting the combination therapy with o-rMETase, a low-methionine diet, FOLFIRI, and bevacizumab, blood CEA levels very rapidly decreased and were almost within the normal limits five months later. CT findings showed the lung metastasis did not grow. Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.

Green synthesis, anti-proliferative evaluation, docking, and MD simulations studies of novel 2-piperazinyl quinoxaline derivatives using hercynite sulfaguanidine-SA as a highly efficient and reusable nanocatalyst.

In this study, the immobilization of sulfaguanidine-SA on the surface of FeAl2O4 (hercynite) MNPs (magnetic nanoparticles) as a novel acid nanocatalyst has been successfully reported for the synthesis of 2-(piperazin-1-yl) quinoxaline derivatives via a one-pot multiple-component reaction under green conditions. The products were characterized by SEM, TEM, TGA, EDS, BET technique, VSM, and FTIR. This series of novel 2-piperazinyl quinoxaline derivatives containing isatin-based thio/semicarbazones and/or Schiff bases of Metformin were evaluated for anticancer activity against both human ovarian and colon-derived tumor cell lines by MTT colorimetric assay. Although most of the investigated hybrid compounds exhibited excellent anti-proliferative activities and high selectivity index (SI) values, the promising compounds N'-[4-(quinoxaline-2-yl)-piperazine-1-yl]methyl-5-chloro-1-H-indole,2,3-dion-3-metformin 4c and N'-[4-(quinoxaline-2-yl)-piperazine-1-yl]methyl-5-bromo-1-H-indole,2,3-dion-3-metformin 4b proved to be the most potent anti-proliferative agents (IC50 values < 1 μM). Molecular docking and dynamics simulation suggest that these hybrid compounds can be wrapped in the catalytic cavity of c-Kit tyrosine kinase receptor and the binding pocket of P-glycoprotein with high scores. Thus, 2-piperazinyl quinoxaline linked isatin-based N-Mannich bases of metformin and/or thio/semicarbazones might be served as suitable candidates for further investigations to develop a new generation of multi-target cancer chemotherapy agents.

Immunogenicity of ChAdOx1-nCoV-19 vaccine in solid malignancy patients by treatment regimen versus healthy controls: A prospective, multicenter observational study.

SummaryBackgroundLimited data exists regarding the efficacy of ChAdOx1-nCoV-19 vaccine against Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in solid cancer patients. We aimed to assess the immunogenicity of the ChAdOx1-nCoV-19 vaccine and the impact of different anticancer therapies for solid malignancies on immune response.MethodsThis prospective, longitudinal observational study of immunogenicity following ChAdOx1-nCoV-19 vaccination among 385 solid cancer patients on active cancer treatment was conducted in two oncology centers. Participants received the first dose between June 18 and July 27, 2021 and the second dose at 8-10 weeks later. Blood samples were evaluated for total immunoglobulins against the receptor-binding of SARS-CoV-2 spike protein (anti-RBD total-Ig) before, and 4-week after the first- and second-doses. The primary endpoint was the geometric mean titers (GMT) of antibody among solid cancer patients compared to healthy controls and the impact of different cancer treatment types.FindingsAmong solid cancer patients, the antibody level increased more slowly to significantly lower levels than achieved in healthy controls. The GMT at 4-weeks post-vaccination in cancer vs. healthy were 224.5 U/ml (95%CI 176.4–285.6) vs. 877.1 U/ml (95%CI 763.5–1008), p<0.0001), respectively. For different types of cancer treatments, chemotherapy agents, especially anthracyclines (GMR 0.004; 95%CI 0.002–0.008), paclitaxel (GMR 0.268; 95%CI 0.123–0.581), oxaliplatin (GMR 0.340; 95%CI 0.165–0.484), and immunotherapy (GMR 0.203; 95%CI 0.109–0.381) showed significantly lower antibody response. Anti-HER2, endocrine therapy and 5-fluouracil or gemcitabine, however, had less impact on the immune response.InterpretationSuboptimal and heterogeneous immunologic responses were observed in cancer patients being treated with different systemic treatments. Immunotherapy or chemotherapy significantly suppressed the antibody response.FundingQuality Improvement Fund, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society and Center of Excellence in Clinical Virology at Chulalongkorn University and Chulalongkorn Medical Oncology Research Fund

In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents

Purpose Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using in silico studies. Methods Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations. Results Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results. Conclusion We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.

The reproductive effects of the cancer chemotherapy agent, Carmofur, on Daphnia magna are mediated by its metabolite, 5-Fluorouracil.

Carmofur is an antineoplastic agent that inhibits ceramidase, a key enzyme in the sphingolipid pathway. Previous research suggests carmofur represses reproductive maturity in Daphnia magna. The purpose of this experiment was to confirm carmofur's effects on fecundity and reproductive maturity over two generations. A chronic toxicity test found reproductive maturity was delayed from 9 to 19 days by 0.80 μM carmofur with a 99.7% drop in reproduction, probably caused by delayed ovarian development. Second generation effects were even greater with 0% reproductive success at 0.40 μM. To our surprise, carmofur was not measured in the media by HPLC 24 h after exposure. Previous research indicated that carmofur is unstable in water and hydrolyzed into 5-fluorouracil (5-FU). Therefore, the chronic toxicity study was repeated with 5-FU and similar effects on reproductive maturity were observed at similar concentrations despite very different acute toxicities (48 h carmofur LC50 = 1.93 μM; 5-FU LC50 = 207 μM). 5-FU delayed reproductive maturity from 9 to 21 days with a 71.12% drop in reproduction at 0.80 μM and greater effects in the 2nd generation similar to carmofur. 5-FU was found stable in aquatic media and HPLC confirmed 5-FU was hydrolyzed from carmofur within 24 h. In conclusion, carmofur and 5-FU reduce fecundity because they delay reproductive maturity and ovarian development in Daphnia magna. We conclude that the reproductive effects observed after carmofur treatment are primarily mediated by its breakdown product, 5-FU. This further underscores the importance of measuring chemical concentrations and evaluating chemical metabolism and decomposition when determining toxicity, especially of chemotherapeutic agents.Clinical trials registration Not applicable.

PD53-02 CYTOTOXICITY CAUSED BY CISPLATIN, VENETOCLAX, AND S63845 TO UROTHELIAL CARCINOMA CELLS EXPANDED IN 3D ORGANOIDS DIFFERS CLEARLY FROM CYTOTOXICITY TO AUTOLOGOUS 2D ADHERENT CELLS

You have accessJournal of UrologyCME1 May 2022PD53-02 CYTOTOXICITY CAUSED BY CISPLATIN, VENETOCLAX, AND S63845 TO UROTHELIAL CARCINOMA CELLS EXPANDED IN 3D ORGANOIDS DIFFERS CLEARLY FROM CYTOTOXICITY TO AUTOLOGOUS 2D ADHERENT CELLS Yi Wei, Bastian Amend, Wilhelm K. Aicher, Arnulf Stenzl, and Niklas Harland Yi WeiYi Wei More articles by this author , Bastian AmendBastian Amend More articles by this author , Wilhelm K. AicherWilhelm K. Aicher More articles by this author , Arnulf StenzlArnulf Stenzl More articles by this author , and Niklas HarlandNiklas Harland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002630.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Organoids are 3-dimensional (3D) constructs reflecting the micro-anatomy of the tissue of origin and some of the cell-cell and cell-matrix interactions observed in vivo. They serve as important tools for research, complementing normal 2-dimensional (2D) cell cultures. The objective of this study was to compare the response of urothelial carcinoma cells to three cancer chemotherapy agents, in a 3D organoid form vs. a conventional 2D culture form, in order to assess if the 3D organoid method is better able to assess the efficacy of chemotherapy agents. METHODS: Bladder cancer tissue was obtained from surgery to produce organoids. Cells were isolated, resuspended in a hydrogel, and incubated in media complemented with ROCK inhibitor Y-27632. To characterize the cells, the expression of urothelial and mesenchymal markers was assessed. To assess cytotoxicity, cisplatin (CIS, 1–30 μM), venetoclax (VTX, 0.6–10 μM), and S63845 (0.6–10 μM) were added to the organoids and incubated for 24, 48, or 72 hours. Cell viability was quantified by CellTiter Glo 3D reagents in a GloMax reader. Untreated organoids and solvent-only samples served as controls. The effects of these components on the autologous cells in 2D cultures were measured using CellTiter Glo 2.0 chemistry. RESULTS: Organoids were established from upper tract urothelial carcinoma (BCO#56) and bladder cancer (BCO#140 and BCO#147) samples. Urothelial markers AE1/AE3, CK5, CK20, and FGFR3 and mesenchymal marker vimentin were expressed in organoids. In drug tests, BCO#56 and BCO#147 yielded different IC50s in organoids compared to corresponding 2D cells towards CIS, VTX, and S63. The IC50s of BCO#140 yielded very similar sensitivities in organoids vs 2D cultures (table). CONCLUSIONS: Two of the three samples tested showed significantly different sensitivity to all three chemotherapy agents tested when assessed in organoids compared to conventional 2D cell cultures Further research is needed to determine if conventional 2D cell culture or newer 3D organoids are the more reliable method for assessing cytotoxicity. Until then, results from either method should not be relied upon, unless they are consistent with results from the other method. Source of Funding: Leuze Stiftung, DFG: GRK2543We thank for proofreading & feedback by Dr. M. Hanna © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e910 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yi Wei More articles by this author Bastian Amend More articles by this author Wilhelm K. Aicher More articles by this author Arnulf Stenzl More articles by this author Niklas Harland More articles by this author Expand All Advertisement PDF DownloadLoading ...

Cardiotoxicity of Non-Anthracycline Cancer Chemotherapy Agents.

Throughout the last decades, newly developed chemotherapeutic agents and immunotherapies that target signaling pathways have provided patients with better prognoses, improved their quality of life and increased survival rates, thus converting cancer to a stable chronic disease. However, non-anthracycline cancer chemotherapy agents and immunotherapies including human epidermal growth factor receptor 2 (HER2) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, Bcr-Abl tyrosine-kinase inhibitors (TKI), proteasome inhibitors, immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T cells) may cause cardiovascular toxicity events and complications that usually interrupt the continuation of an appropriate treatment regimen, which induces life-threatening risks or leads to long-term morbidity. Heart failure, cardiac arrythmias and cardiomyopathies are the most common cardiovascular events related to cardiotoxicity due to chemotherapy. Each patient should be carefully assessed and monitored before, during and after the administration of chemotherapy, to address any predisposing risk factors and the new onset of cardiotoxicity manifestations early and treat them appropriately. The development of novel anticancer agents that cause minimal cardiovascular toxicity events or novel agents that ameliorate the adverse effects of the existing anticancer agents could drastically change the field of cardio-oncology. The aim of this narrative review is to demonstrate new knowledge regarding the screening and diagnosis of non-anthracycline-induced cardiotoxicity and to propose protective measures that could be performed in order to achieve the delivery of optimal care.

The Role of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 Regulatory Loop in Cervical Cancer Cell Growth and Resistance to Cisplatin.

Cervical cancer is a highly prevalent female malignancy. Presently, cisplatin (DDP) is a first-line agent for cervical cancer chemotherapy. However, its curative effect is limited because of chemo-resistance. It has been previously reported that SOX9 targeted and activated oncogenic genes, enhancing cervical cancer cell resistance to DDP. The effects of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop on cervical cancer cell growth and resistance to DDP have been demonstrated. miR-361-3p expression was decreased in DDP-resistant cervical cancer cells and tissues. Moreover, miR-361-3p overexpression inhibited the growth of resistant cervical cancer cells and the resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR-361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition were partially reversed by SOX9 knockdown. LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues. LncRNA ANXA2P2 inhibited miR-361-3p expression by binding, thereby upregulating SOX9. LncRNA ANXA2P2 knockdown inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas the effects of lncRNA ANXA2P2 knockdown were partially reversed by miR-361-3p inhibition. SOX9 expression was elevated in DDP-resistant cervical cancer cells and tissues, and SOX9 activated lncRNA ANXA2P2 transcription by binding. Collectively, SOX9, lncRNA ANXA2P2, and miR-361-3p form a regulatory loop, modulating DDP-resistant cervical cancer cell growth and response to DDP treatment.