Anticancer Research Articles

Isolation and Characterization of Cytotoxic Compounds from Detarium microcarpum Guill. and Perr. Stem Bark.

Globally, about 8.2 million cancer-related deaths are recorded annually. Sadly, most of the deaths result from the toxicity of most chemotherapeutic agents. Hence, there are growing demands for chemotherapeutic agents with high specificity and selectivity. This study was designed to assess the cytotoxic potential of Detarium microcarpum and isolate cytotoxic compounds with better selectivity profiles. Detarium microcarpum Stem bark (DMS) was collected and authenticated at the Forest Herbarium Ibadan (FHI), and a voucher (FHI-111954) was issued. Dried DMS was pulverized and extracted into 70% methanol. The extract was partitioned into hexane, dichloromethane, and ethyl acetate fractions. The cytotoxicities of the extract, fractions, and isolated compounds were determined. The cytotoxicity of the isolated compounds was tested against different cell lines, including human breast (AU565 and MDA MB231), oral adenosquamous (CAL27), and cervical (HeLa) cancer cells, as well as healthy (3T3) non-cancer cells. Methyl gallate, eriodictyol, quercetin, quebrachitol, catechin, catechin gallate, and gallic acid, isolated from dichloromethane and ethyl acetate fractions, displayed weak cytotoxicity against breast (AU565 and MDAMD-231) and cervical (HeLa) cancer cell lines. Interestingly, all the compounds, except gallic acid (48.91±4.51% inhibition), displayed potent cytotoxicity on oral cancer cells. Methyl gallate and quercetin displayed the highest activity, with IC50 values of 89.57±1.98µM and 78.19±1.49µM, respectively. Interestingly, all the compounds were not toxic to healthy non-cancer (3T3) cells. The compounds displayed anticancer activity specific to oral cancer cells and were highly selective for cancer cells without causing significant toxicity to healthy non-cancer cells.

Metformin in combination with chemotherapy increases apoptosis in gastric cancer cells and counteracts senescence induced by chemotherapy.

Gastric cancer (GC) is the fourth leading cause of cancer death in the world, and there is a demand for new therapeutic agents to treat GC. Metformin has been demonstrated to be an antineoplastic agent in some types of cancer; however, it has not been sufficiently valued in treating GC because the effect of metformin in combination with chemotherapy regimens has not yet been evaluated. The present study aimed to evaluate the mechanisms underlying cell death induced by metformin alone or when combined with chemotherapy. The cytogenetic characteristics of the NCI-N87 cell line were determined by fluorescence in situ hybridization (FISH). To determine viability, the cells were treated with metformin, epirubicin, cisplatin, docetaxel and 5-fluorouracil (individually and at different concentrations). Subsequently, the cells were treated with metformin alone, and in combination with the chemotherapeutic drugs and the epirubicin + cisplatin + 5-fluorouracil, docetaxel + cisplatin + 5-fluorouracil, and cisplatin + 5-fluorouracil regimens. Cell viability, proliferation and mitochondrial membrane potential (ΔΨm) were analyzed by spectrophotometry. Apoptosis, caspase activity and cell cycle progression were assessed by flow cytometry. Finally, light microscopy was used to evaluate senescence and clonogenicity. The results revealed that metformin, alone and when combined with chemotherapy, increased the proportion of apoptotic cells, promoted the loss of ΔΨm, and induced apoptosis through caspase activity in GC cells. Moreover, metformin decreased cell proliferation. In addition, metformin alone did not induce senescence and it counteracted the effects of chemotherapy-induced senescence in GC cells. Additionally, metformin, alone and when combined with chemotherapy, decreased the clonogenic capacity of NCI-N87 GC cells. In conclusion, metformin may increase the effects of chemotherapy on NCI-N87 cell death and could represent an option to improve the treatment of GC.

Pyrazole Paradigms: Unveiling Synthetic Pathways and Unraveling Anti-Cancer Potential.

This review investigates the synthetic methods and anti-cancer activities of pyrazole compounds. Various synthetic approaches, including traditional organic synthesis and microwaveassisted synthesis, have been used to change the pyrazole core structure, resulting in new compounds with improved pharmacological properties. The paper also covers the mechanisms of action that underpin pyrazole derivatives' anti-cancer characteristics, focusing on interactions with major molecular targets implicated in cancer growth and proliferation. SAR insights help to rationally develop novel anti-cancer drugs. In conclusion, the review emphasizes the versatility of pyrazole derivatives as scaffolds for the discovery and development of new anti-cancer medicines. By understanding synthesis routes and unravelling anti-cancer potential, this study hopes to encourage new research endeavours focused on leveraging the therapeutic advantages of pyrazole paradigms in the fight against cancer.

Targeting Cervical Cancer Stem Cells by Phytochemicals.

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

Dysprosium-containing Cobalt Sulfide Nanoparticles as Anticancer Drug Carriers.

Among various materials designed for anticancer drug transport, sulfide nanoparticles are uniquely intriguing owing to their spectral characteristics. Exploration of newer nanoscale copper sulfide particles with dysprosium doping is reported herein. It leads to a change in the physicochemical properties of the sulfide nanoparticles and hence the difference in drug release and cytotoxicity. We intend to purport the suitably engineered cobalt sulfide and dysprosium-doped cobalt sulfide nanoparticles that are magnetic and NIR-absorbing, as drug delivery vehicles. The drug loading and release are based on the supramolecular drug complex formation on the surface of the nanoparticles. The nanomaterials are synthesized employing hydrothermal procedures, coated with a biocompatible poly-β-cyclodextrin, and characterized using the methods of diffractometry, microscopy, spectroscopy, thermogravimetry and magnetometry. The sustained drug release is investigated in vitro. 5-Fluorouracil is loaded in the nanocarriers. The empty and 5-fluorouracil-loaded nanocarriers are screened for their anti-breast cancer activity in vitro on MCF-7 cells. The size of the nanoparticles is below 10 nm. They show soft ferromagnetic characteristics. Further, they show broad NIR absorption bands extending up to 1200 nm, with the dysprosium-doped material displaying greater absorbance. The drug 5-fluorouracil is encapsulated in the nanocarriers and released sustainably, with the expulsion duration extending over 10 days. The IC50 of the blank and the drug-loaded cobalt sulfide are 16.24 ± 3.6 and 12.2 ± 2.6 μg mL-1, respectively. For the drug-loaded, dysprosium-doped nanocarrier, the IC50 value is 9.7 ± 0.3 μg mL-1. The ultrasmall nanoparticles possess a size suitable for drug delivery and are dispersed well in the aqueous medium. The release of the loaded 5-fluorouracil is slow and sustained. The anticancer activity of the drug-loaded nanocarrier shows an increase in efficacy, and the cytotoxicity is appreciable due to the controlled release. The nanocarriers show multi-functional characteristics, i.e., magnetic and NIR-absorbing, and are promising drug delivery agents.

Theranostic Nanomaterials to Overcome the Challenges in Peptide-based Cancer Therapy

: Globally, the number of cancer cases and death rates are increasing, making it necessary to develop new and improved medications for the treatment of cancer.Owing to a broad range of physio-chemical properties, Antimicrobial Peptides (AMPs) possessing tumoricidal properties and Anticancer Peptides (ACPs) are promising alternatives for enhanced cancer therapy. Recently, biopharmaceuticals have changed the rules of radiation therapy and chemotherapy by introducing peptide therapy for cancer treatments. However, several limitations obstruct the clinical efficacy of peptide-based cancer therapies, which include limited target specificity, oral intake, and half-life payloads. The integration of theranostic nanomaterials could be facilitated as a transformative strategy to address these challenges and enhance the potential of peptide-based cancer therapy. Increasing applications of recent times of peptide-nano hybrids have addressed the crucial issues related to conventional peptide-based drug therapy by enhancing the druggability. This review aims to explore the impact of nano-formulated peptides as an anticancer agent, highlighting the involvement of nanotechnology as an enabling tool.

Evaluation of the in vivo acute toxicity and in vitro genotoxicity and mutagenicity of synthetic β-carboline alkaloids with selective cytotoxic activity against ovarian and breast cancer cell lines

The aim of this study was to evaluate the in vitro cytotoxic, genotoxic, and mutagenic potential and to determine the in silico ADME parameters of two synthetic β-carboline alkaloids developed as prototypes of antitumor agents (NQBio-06 and NQBio-21). Additionally, acute toxicity of the compounds was evaluated in mice. The results from the MTT assay showed that NQBio-06 presented higher cytotoxicity in the ovarian cancer cell line TOV-21G (IC50 = 2.5 µM, selectivity index = 23.7). NQBio-21 presented an IC50 of 6.9 µM and a selectivity index of 14.5 against MDA-MB-231 breast cancer cells. Comet assay results showed that NQBio-06 did not induce chromosomal breaks in vitro, but NQBio-21 was genotoxic with and without metabolic activation (S9 fraction). Micronucleus assay showed that both compounds were mutagenic. In addition, metabolic activation enhanced this effect in vitro. The in silico predictions showed that the compounds met the criteria set by Lipinski's rules, had strong prediction for intestinal absorption, and were possible substrates for P-glycoprotein. The in vivo results demonstrated that both the compounds exhibited low acute toxicity. These results suggest that the mechanisms underlying the cytotoxicity of NQBio-06 and NQBio-21 are related to DNA damage induction and that the use of S9 enhanced these effects. In vivo analysis showed signs of toxicity after a single administration of the compounds in mice. These findings highlight the potential of β-carboline compounds as sources for the development of new anticancer chemotherapeutic agents.

Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets.

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

Protective Effect of Memantine on Cisplatin-Induced Ototoxicity: An In Vitro Study.

Memantine, an N -methyl- d -aspartate receptor antagonist, is widely used to treat Alzheimer's disease and has been found to have potential neuroprotective effects. In this study, we evaluated the protective effects of memantine against cisplatin-induced ototoxicity. Cisplatin is a widely used anticancer drug for various cancers; however, its use is limited by its side effects, including ototoxicity. Several drugs have been developed to reduce cisplatin toxicity. In this study, we treated cisplatin-damaged cochlear hair cells with memantine and evaluated its protective effects. House Ear Institute Organ of Corti 1 (HEI-OC1) cells and cochlear explants were treated with cisplatin or memantine. Cell viability, apoptotic patterns, reactive oxygen species (ROS) production, Bcl-2/caspase-3 activity, and cell numbers were measured to evaluate the anti-apoptotic and antioxidative effects of memantine. Memantine treatment significantly improved cell viability and reduced cisplatin-induced apoptosis in auditory cells. Bcl-2/caspase-3 activity was also significantly increased, suggesting anti-apoptotic effects against cisplatin-induced ototoxicity. Our results suggest that memantine protects against cisplatin-induced ototoxicity in vitro, providing a potential new strategy for preventing hearing loss in patients undergoing cisplatin chemotherapy.

The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

Electrocoagulation-photocatalysis sequential combined method for the removal of anticancer drugs from pharmaceutical wastewater using NH2-MIL-125(Ti)/cobalt ferrite nanorods composite photocatalyst

Electrocoagulation-photocatalysis sequential combined method for the removal of anticancer drugs from pharmaceutical wastewater using NH2-MIL-125(Ti)/cobalt ferrite nanorods composite photocatalyst

Optimizing the Extraction of Polyphenols from the Bark of Terminalia arjuna and an In-silico Investigation on its Activity in Colorectal Cancer.

The interconnection between different fields of research has gained interest due to its cutting-edge perspectives in solving scientific problems. Terminalia arjuna is indigenously used in India for curing several diseases, and its pharmacological activities are being revisited in recent drug-repurposing research. Efficient ultrasound-assisted extraction of phytochemicals from the bark of Terminalia arjuna is highlighted in this study. Following the optimization of the extraction process, the crude hydroethanolic extract is subjected to phytochemical profiling and an in-silico investigation of its anti-cancer properties. A three-level four-factor Box-Behnken design is exploited to optimize four operational parameters, namely extraction time, ultrasonic power, ethanol concentration (as the extracting solvent) and solute (in g): solvent (in mL) ratio. At the optimum parametric condition, the crude extract is obtained, and its GC-MS analysis is carried out. An analysis of network pharmacology (by constructing and visualizing biological networks using Cytoscape) combined with molecular docking reveals the potential antineoplastic targets of the crude extract. The ANOVA table exhibits the significance, adequacy and reliability of the proposed second-order polynomial model with the R² value of 0.917 and adjusted R² of 0.865. Experimental results portray the significant antioxidant potential of the prepared extract in its crude form. The GC-MS analysis of the crude extract predicts the extracted phytochemicals, while the constructed biological networks highlight its multi-targeted activity in colorectal cancer. The study identifies three phytochemicals viz. luteolin, β-sitosterol and arjunic acid as potent anti-cancer agents and can be extended with in-vitro and in-vivo experiments to validate the in-silico results, thus establishing lead phytochemicals in multi-targeted colorectal cancer therapies.

Nature's Elixir for Cancer Treatment: Targeting Tumor-induced Neovascularization.

Angiogenesis, a multistep process, involves sprouting of new vessels from the pre-existing vessels in response to a stimulus in its microenvironment. Normally, angiogenesis is important for tissue maintenance and homeostasis, however it is also known to be associated with various pathologies, including cancer. Importantly, neovascularization is very crucial for tumors to grow and metastasize since it allows delivery of oxygen and nutrients as well as promotes tumor cell dissemination to distant sites. Activation of angiogenic switch is a consequence of imbalance in pro- as well as anti-angiogenic factors, that are immensely impacted by reactive oxygen species and epigenetic regulation. Several reports have suggested that angiogenic inhibitors significantly inhibit tumor growth. Therefore, anti-angiogenic therapy has gained substantial attention and has been considered a rational approach in cancer therapeutics. In this line, several anti- angiogenic drugs have been approved, however, their long term usage caused several side effects. In view of this, researchers switched to plant-based natural compounds for identifying safe and cost-effective anti-angiogenic drugs. Of note, various phytochemicals have been evaluated to reduce tumor growth by inhibiting tumor-induced angiogenesis. Moreover, the implication of nano-carriers to enhance the bioavailability of phytochemicals has proven to be more efficient anti-cancer agents. The present review highlights the existing knowledge on tumor-induced neovascularization and its regulation at the epigenetic level. Further, we emphasize the inhibitory effect of phytochemicals on tumor- induced angiogenesis that will open up new avenues in cancer therapeutics.

Activation of SIRT3 by Tanshinone IIA ameliorates renal fibrosis by suppressing the TGF-β/TSP-1 pathway and attenuating oxidative stress.

Although doxorubicin (DOX) is a common chemotherapeutic drug, the serious nephrotoxicity caused by DOX-induced renal fibrosis remains a considerable clinical problem. Tanshinone IIA (Tan IIA), a compound extracted from Salvia miltiorrhiza, has been reported to have an anti-fibrotic effect. Therefore, this study investigated the molecular pathway whereby Tan IIA protects the kidneys from DOX administration. DOX (3mg/kg body weight) was intraperitoneally administered every 3 d for a total of 7 injections (cumulative dose of 21mg/kg) to induce nephrotoxicity. Then, Tan IIA (5 or 10mg/kg/d) was administered by intraperitoneal injection for 28 d. In an in vitro study, 293T cells were cultured and treated with DOX and Tan IIA for 24h. Tan IIA reduced the blood urea nitrogen levels elevated by DOX while increasing superoxide dismutase activity, down-regulating reactive oxygen species, ameliorating renal-tubule thickening, and rescuing mitochondrial morphology. Additionally, Tan IIA reduced the renal collagen deposition, increased ATP production and complex-I activity, down-regulated transforming growth factor-β1 (TGF-β1) and thrombospondin-1 (TSP-1), and up-regulated sirtuin 3 (SIRT3). Tan IIA significantly increased cell viability. Additionally, RNA interference was employed to silence the expression of SIRT3, which eliminated the effect of Tan IIA in suppressing the expression of TGF-β1 and TSP-1. In conclusion, Tan IIA ameliorated DOX-induced nephrotoxicity by attenuating oxidative injury and fibrosis. The Tan IIA-induced rescue of mitochondrial morphology and function while alleviating renal fibrosis may be associated with the activation of SIRT3 to suppress the TGF-β/TSP-1 pathway.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment

BACKGROUND Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. AIM To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. METHODS This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2 , PLAU , and CCNA2 . The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. RESULTS The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (bP < 0.01), moderately associated with tumor stage (T) (aP < 0.05), and significantly correlated with residual tumor (R) status (bP < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. CONCLUSION The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Medical dilemma: Programmed death 1 blockade (sintilimab) therapy in patients suffering from tumours combined with psoriasis

Tumour immunotherapy represented by immune checkpoint inhibitors (ICIs) has greatly improved the overall prognosis of patients with malignant tumours, and is regarded as an important breakthrough in the field of medicine in recent years. ICIs have gradually become the core of tumour therapy and are increasingly used in the clinic. In order to achieve early clinical prediction and management of immune-related adverse events (irAEs), it is still necessary to perform further research on the mechanisms, risk factors, and predictors of irAE occurrence in the future. Zhou et al describe the consultation of a patient with advanced gastric cancer combined with chronic plaque psoriasis. This case provides an important reference for the use of programmed cell death protein-1 (PD-1) inhibitors in patients of tumours combined with chronic plaque psoriasis. This case also highlights that screening of high-risk groups for irAEs is critical before applying PD-1 inhibitors to patients with chronic psoriasis combined with tumours. PD-1 inhibitors are new and potent antineoplastic agents that can cause serious immune-related adverse events such as toxic epidermal necrolysis release and psoriasis. Glucocorticosteroids are the first-line agents for irAEs. The incidence of rheumatic irAEs may be higher in reality, which will inevitably become a new challenge for rheumatologists and dermatologists.

Expedited program and utilization for anticancer drug approval in China and the United States

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Chinese expert consensus on the systemic treatment of advanced clear cell renal cell carcinoma (2024 edition)

Renal cell carcinoma (RCC) accounts for approximately 2% to 3% of malignant tumors in adults, with a male-to-female ratio of approximately 1.5∶1 worldwide. It can occur in all age groups, with a peak incidence in the 60-70 age range, and the median age is approximately 64 years. The current causes of kidney cancer are still unclear, but smoking, obesity, hypertension, and some genetic factors are considered risk factors for kidney cancer development. Conducive to the gradual popularization of physical examination and screening, more and more patients with kidney cancer are being detected and treated in the early stages. However, nearly 30% of patients still have locally advanced or metastatic kidney cancer at the time of initial diagnosis. Traditional chemotherapy drugs are generally ineffective for advanced RCC, and currently, advanced RCC is mainly treated with anti-vascular and immunotherapy. At present, first-line treatment is mostly stratified based on clinical characteristics such as International mRCC Database Consortium (IMDC) prognosis risk, and there are multiple options available, including anti vascular therapy, anti-vascular combined immunotherapy, and dual immunotherapy. Subsequently, first-line treatment often selects drugs based on the composition, effectiveness, and safety of first-line treatment plans. In recent years, research has found that the molecular typing and metastasis characteristics of RCC also affect the prognosis of patients, leading to many controversies in the treatment of advanced RCC. This consensus is guided by the controversial clinical issues in the management of advanced RCC. After discussion and voting by multidisciplinary clinical experts, a consensus of 10 clinical issues has been reached. At the same time, experts recommend domestic clinical and research institutions to lead or participate in more large-scale clinical trials, providing more basis for clinical decision-making and the selection of the best beneficiaries.

Abstract C054: Current anticancer drugs differentially impact Black and White prostate cancer cell lines

Abstract Introduction/Background: In pre-clinical models of prostate cancer (PCa) such as the utilization of cell lines, it is important to address the limited diversity present. This acknowledgment is vital to facilitate equitable assessment of the efficacy and safety of drug development across various races and ethnicities. Of all commercially available PCa cell lines, 98% of them are of European origin. The genetic and biological disparities between PCa cell lines derived from men of European ancestry (MEA) and men of African ancestry (MAA) may underlie the observed enhanced responsiveness of tumours to existing anticancer agents in MEA compared to MAA. This difference is notable given that MAA are 2.5 times more likely to succumb to PCa. This study compared the cytotoxic effects of five anticancer drugs (Docetaxel, Cabazitaxel, Abiraterone, Olaparib, Enzalutamide) and the natural product betaine on MAA (ACRJ-PC28, MDA-PCA-2b) and MEA (DU-145, PC-3) PCa cell lines. Method: After a 72-hour treatment with the anti-cancer drugs and the natural product, the inhibitory effects of these anti-cancer agents on the four cell lines were investigated using three different assays. CellTiter Aqueous, Neutral Red, and Crystal Violet assays were utilized due to distinct growth patterns observed in the various cell lines. By comparing the optical density (OD) readings and examining the cellular morphology through microscopic visualization, we aimed to determine which assay(s) yielded the most reliable results in determining accurate IC50 values. Results: Drug selectivity was observed for Abiraterone and Olaparib that were most effective in ACRJ-PC28 (IC50 = 1.10 μM) and PC-3 (IC50 = 0.28 μM) cells compared to the other PCa cell lines. Enzalutamide differentially impacted MAA, (IC50= 206 μM for ACRJ-PC28 and 104 μM for MDA-PCA-2b) and MEA (IC50 = 37 μM for PC-3 and 48 μM for DU-145) PCa cell lines. However, no distinct impact was observed for Docetaxel (IC50s = 0.05 nM for ACRJ-PC28; 0.08 nM for MDA-PCA-2b, 0.07 nM for PC-3 and 0.08 nM for DU-145) and Cabazitaxel ((IC50s = 0.56 nM for ACRJ-PC28; 0.45 nM for MDA-PCA-2b, 0.43 nM for PC-3 and 0.38 nM for DU-145) as both drugs impacted the cell lines very potently in the nM range. Conclusion: Due to the heterogenous nature of cancers, especially in PCa, a single drug or drug class may not be the best course of treatment. Instead, a combination of drugs with different mechanisms may be more suitable for addressing the diversity in cancer types. This points to the evolving understanding of personalized cancer treatment, where a strategic integration of first, second, and third-line therapies can effectively address the genetic and epigenetic factors that are unique to individuals in cancer management. Citation Format: Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Rory Thompson, Belinda Morison, Valerie Marah, Camille Ragin. Current anticancer drugs differentially impact Black and White prostate cancer cell lines [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C054.

Abstract C109: Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American

Abstract Cancer cells have an increased glucose metabolism, primarily characterized by augmented glucose uptake and aerobic glycolysis, converting glucose into pyruvate, eventually producing lactate. Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of death among women in the United States. The triple-negative breast cancer (TNBC) subgroup is the most aggressive, metastatic, and refractory because of the absence of the three characteristic receptors: Estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu), representing approximately 10-15% of all BC cases. Racial disparities analysis demonstrates that African American (AA) has a higher incidence of TNBC subtype, with an earlier onset, more advanced stage, more aggressive histologic features, and poor survival, compared to other ethnic groups. Hyperglycemia affects the cancer progression through metabolic reprogramming and molecular alterations. AA women with Type 2 diabetes (T2D) are at increased risk of developing ER-negative BC. The reasonable combination therapy of metformin with NF-𝜅Bi and MCT4i, is promising because it can rapidly disable tumor cell growth but with a minor effect on normal cells, holding promise as an anti-BC treatment. Because of the potential side effects of MCT4 inhibitors and the potent inhibitory effect of microRNA on target genes, we consider using microRNA instead of inhibitors to suppress MCT4 expression. We will investigate the anti-diabetes-associated TNBC effect of the MRS, consisting of blocking lactate export via MCT4 degradation by miR-206, in combination with promoting lactate production via forcing glycolysis with metformin and NF-𝜅Bi treatment, in a preclinical study of AA women. Moreover, our previous study and other studies have also shown an elevated expression of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) in BC tissues and cells, particularly in metastatic TNBC. We will also explore the molecular mechanisms by which high glucose (HG) leads to lactate accumulation in BC cells. Our overall strategy is that excessive glucose uptake upregulates the MCT4 through a MALAT1/miR-206/MCT4 axis, miR-206-directed MRS shifts glucose metabolism from Oxidative phosphorylation (OXPHOS) to glycolysis, increasing lactate production. Meanwhile, blocking the export of excessive lactate through MCT4 degradation causes high intracellular lactate accumulation and a decrease in intracellular pH (pHi), resulting in metabolic crisis and BC cell death. Due to a complex interplay between hyperglycemia and cancer, antihyperglycemic drugs have often been devised in combination with anticancer drugs for cancer treatment. Our proposed approach will broadly impact the field by providing a novel idea for therapies targeting cancer cell lactate metabolism. In the long term, these studies may reveal an effective therapeutic strategy for diabetes-associated BC, especially in AA women. Citation Format: Qiongyu Hao, Yong Wu, Yanyuan Wu, Jaydutt Vadgama. Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C109.