Potential Cancer Therapeutic Agent Research Articles

Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling

Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling

Construction and anti-pancreatic cancer activity of selenium nanoparticles stabilized by Prunella vulgaris polysaccharide

Selenium nanoparticles (SeNPs), as a potential cancer therapeutic agent, have attracted extensive attention due to their high anticancer activity and low toxicity. Polysaccharides could be the modifiers and stabilizers to improve the stability and dispersibility of SeNPs in aqueous solution. This study aimed to investigate the physicochemical characterization, stability, and anti-pancreatic cancer cell activities of SeNPs stabilized by a heteroxylan PVP3-1 extracted from the clusters of Prunella vulgaris Linn. Our results showed that PVP3-1 with Mw of 154 kDa was composed of →4)-β-D-Xylp(1→, →2, 4)-β-D-Xylp(1→, t-α-L-Araf(1→ and 4-MeO-α-D-GlcpA(1→. Red, zero-valent, and uniform spherical SeNPs with an average diameter of about 60 nm and high stability in aqueous solution were constructed successfully by polysaccharide PVP3-1. Anti-pancreatic cancer cell activity assays showed that PVP3-1-SeNPs could inhibit the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, PVP3-1-SeNPs induced apoptosis and autophagy of pancreatic cancer cells through inhibiting mTOR signaling pathway. In conclusion, these results indicated that PVP3-1-SeNPs could be potential anti-tumor nanoparticles for treating pancreatic cancer.

악성 흑색종에서 CGM이 유도하는 세포자멸사와 상피간엽이행 억제 효과

Objectives: This study explored the effects of CGM treatment on malignant melanoma cells, specifically by focusing on its ability to induce apoptosis and alter the expression of proteins involved in epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. Methods: To assess cell viability and proliferation rates, at MTT assay and colony formation assay were performed. FACS analysis was conducted to confirm cell apoptosis, and JC-1 fluorescent staining was executed. An invasion assay was performed to observe cell invasiveness, and protein expression was validated by western blot analysis. Results: Our findings demonstrated that CGM treatment significantly induced apoptosis in malignant melanoma cells. Additionally, CGM treatment markedly reduced the invasiveness of melanoma cells, as observed in the invasion assays. Western blot analysis revealed that CGM modulated the expression of several critical proteins involved in EMT, thereby disrupting the EMT process which is essential for cancer metastasis. Conclusions: The research findings indicate that CGM inhibits the growth of melanoma effectively induces apoptosis of cancer cells, and suppresses metastasis through EMT inhibition. Therefore, CGM demonstrates significant value as a potential cancer therapeutic agent.

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises.

Throughout human history, the utilization of medicinal herbs has been recognized as a crucial defense against various ailments, including cancer. Natural products with potential anticancer properties, capable of inducing apoptosis in cancer cells, have garnered substantial attention. One such agent under investigation is guggulsterone (GS), a phytosterol derived from the gum resin of the Commiphora mukul tree. This review aims to provide a comprehensive summary of recent studies elucidating the anticancer molecular mechanisms and molecular targets of GS, guiding future research and potential applications as an adjuvant drug in cancer therapy. Recent in vivo and in vitro studies have explored the biological activities of the active ingredients in Commiphora mukul. Specifically, GS emerges as a potential cancer chemopreventive and therapeutic agent. The investigations delve into the impact of GS on constitutively activated survival pathways, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-kappa B (NF-kB), and PI3-kinase/AKT signaling pathways. These pathways regulate antiapoptotic and proinflammatory genes, exerting control over growth and inflammatory responses. The findings highlight the potential of GS in disrupting survival pathways crucial for cancer cell viability. The inhibition of JAK/STAT, NF-kB, and PI3-kinase/AKT signaling pathways positions GS as a promising candidate for cancer therapy. The review synthesizes evidence from diverse studies, underscoring the multifaceted biological activities of GS in cancer prevention and treatment. To advance our understanding, future clinical and translational studies are imperative to determine effective doses in humans. Additionally, there is a need for the development of new pharmaceutical forms of GS to optimize therapeutic effects. This comprehensive review provides a foundation for ongoing research, offering insights into the potential of GS as a valuable addition to the armamentarium against cancer.

Abstract B005: In-silico identification of oxa/thiazole carboxamides as potential breast cancer therapeutic agents with vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitory effect

Abstract Vascular Endothelial Growth Factor Receptor (VEGFR-2) is a tyrosine kinase receptor mainly known to be expressed in vascular endothelial cells. Overexpression of VEGFER-2 has been linked to tumor angiogenesis, necessitating the need for VEGFER-2 inhibitors. In-silico screening of oxa/thiazole carboxamide scaffold-bearing compounds retrieved from the ZINC database was conducted to identify potential anticancer agents with VEGFR-2 inhibitory effect. The interaction of VEGFR2 with tivozanib was used to generate a six-point pharmacophore model for screening ZINC chemical database. The virtual screening for potential VEGFR2 inhibitors generated 48 hits. The hits were filtered and ranked using molecular docking, drug-likeness, and absorption, distribution, metabolism, and excretion (ADME) protocols. The molecular docking results displayed ten compounds that adapted a similar binding mode and orientation within the active site of the VEGFR2 receptor. The molecular dynamic (MD) simulation analysis of the best hit, 3C, was carried out to validate the docking data. The RMSD and RMSF analysis was used to explain the stability of the VEGFR2 and 3c during the 50 ns simulation trajectory. The MD output revealed that the complex maintained conformational stability and consistent flexibility throughout the run. The results of the docking and simulation techniques supported each other. Thus, 3c emerged as a promising oxa/thiazole carboxamide-carrying lead molecule in our search for potential triple-negative breast cancer therapy. Citation Format: Steven M. Ewell, Getinet Mequanint, Donald Sikazwe, Kinfe Redda, Bereket Mochona. In-silico identification of oxa/thiazole carboxamides as potential breast cancer therapeutic agents with vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitory effect [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B005.

Cyclic anthraquinone derivatives, unique G-quadruplex binders, selectively induce cancer cell apoptosis and inhibit tumor growth.

Cyclic anthraquinone derivatives (cAQs), which link two side chains of 1,5-disubstituted anthraquinone as a threading DNA intercalator, have been developed as G-quartet (G4) DNA-specific ligands. Among the cAQs, cAQ-mBen linked through the 1,3-position of benzene had the strongest affinity for G4 recognition and stabilization in vitro and was confirmed to bind to the G4 structure in vivo, selectively inhibiting cancer cell proliferation in correlation with telomerase expression levels and triggering cell apoptosis. RNA-sequencing analysis further indicated that differentially expressed genes regulated by cAQ-mBen were profiled with more potential quadruplex-forming sequences. In the treatment of the tumor-bearing mouse model, cAQ-mBen could effectively reduce tumor tissue and had less adverse effects on healthy tissue. These results suggest that cAQ-mBen can be a potential cancer therapeutic agent as a G4 binder.

Ferumoxytol-Enhanced MRI in Children and Young Adults: State of the Art.

Ferumoxytol is an ultrasmall iron oxide nanoparticle that was originally approved by the FDA in 2009 for IV treatment of iron deficiency in adults with chronic kidney disease. Subsequently, its off-label use as an MRI contrast agent increased in clinical practice, particularly in pediatric patients in North America. Unlike conventional MRI contrast agents that are based on the rare earth metal gadolinium (gadolinium-based contrast agents), ferumoxytol is biodegradable and carries no potential risk of nephrogenic systemic fibrosis. At FDA-approved doses, ferumoxytol shows no long-term tissue retention in patients with intact iron metabolism. Ferumoxytol provides unique MRI properties, including long-lasting vascular retention (facilitating high-quality vascular imaging) and retention in reticuloendothelial system tissues, thereby supporting a variety of applications beyond those possible with gadolinium-based contrast agents (GBCAs). This Clinical Perspective describes clinical and early translational applications of ferumoxytol-enhanced MRI in children and young adults through off-label use in a variety of settings, including vascular, cardiac, and cancer imaging, drawing on the institutional experience of the authors. In addition, we describe current advances in pre-clinical and clinical research using ferumoxytol in cellular and molecular imaging as well as the use of ferumoxytol as a novel potential cancer therapeutic agent.

A novel antimicrobial peptide M1-8 targets the lysosomal pathway to inhibit autolysosome formation and promote apoptosis in liver cancer cells.

Lysosomes, a central regulator of autophagy, play a critical role in tumour growth. Lysosomal protease cathepsin D can initiate apoptosis when released from lysosomes into the cytosol. In this study, we observed that Musca domestica cecropin (Mdc) 1-8 (M1-8), a small anti-tumour peptide derived from Mdc, inhibits hepatoma cell growth by blocking autophagy-lysosome fusion. This effect is likely achieved by targeting lysosomes to activate lysosomal protease D. Additionally, we examined whether lysosomal content and cathepsin D release were involved in M1-8-induced apoptosis. After exposure to M1-8, human hepatoma HepG2 cells rapidly co-localized with lysosomes, disrupted lysosomal integrity, caused leakage of lysosomal protease cathepsin D, caspase activation and mitochondrial membrane potential changes; and promoted cell apoptosis. Interestingly, in M1-8-treated HepG2 cells, autophagic protein content increased and the lysosome-autophagosome fusion was inhibited, suggesting that M1-8 can cause apoptosis through autophagy and lysosomes. This result indicates that a small accumulation of autophagy and autolysosome inhibition in cells can cause cell death. Taken together, these data suggest a novel insight into the regulatory mechanisms of M1-8 in autophagy and lysosomes, which may facilitate the development of M1-8 as a potential cancer therapeutic agent.

A Mulberry Diels-Alder-Type Adduct, Kuwanon M, Triggers Apoptosis and Paraptosis of Lung Cancer Cells through Inducing Endoplasmic Reticulum Stress.

The mulberry tree (Morus alba) has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of Morus alba. This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome c and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.

Fabrication of an Au-doped Cu/Fe oxide-polymer core–shell nanoreactor with chemodynamic and photodynamic dual effects as potential cancer therapeutic agents

Nanoparticles are widely used in biomedical applications and cancer treatments due to their minute scale, multi-function, and long retention time. Among the various nanoparticles, the unique optical property derived from the localized surface plasmon resonance effect of metallic nanoparticles is a primary reason that metallic nanoparticles are researched and applied. Copper and Iron nanoparticles have the potential to generate hydroxyl radicals in excess H2O2 via Fenton or Fenton-like reactions. On the other hand, gold nanoparticles equipped with a photosensitizer can transfer the energy of photons to chemical energy and enhance the production of singlet oxygen, which is suitable for cancer treatment. With the actions of these two reactive oxygen species in the tumor microenvironment, cell apoptosis can further be induced. In this work, we first synthesized dual metal nanoparticles with poly[styrene-alt-(maleic acid, sodium salt)(Cu ferrite oxide-polymer) by a simple one-step hydrothermal reduction reaction. Then, gold(III) was reduced and doped into the structure, which formed a triple metal structure, Au-doped Cu ferrite nanoparticles (Au/Cu ferrite oxide-polymer NPs). The metal ratio of the product could be controlled by manipulating the Fe/Cu ratio of reactants and the sequence of addition of reactants. The core–shell structure was verified by transmission electron microscopy. Moreover, the hydroxyl radical and singlet oxygen generation ability of Au/Cu ferrite oxide-polymer was proved. The chemodynamic and photodynamic effect was measured, and the in vitro ROS generation was observed. Furthermore, the behavior of endocytosis by cancer cells could be controlled by the magnetic field. The result indicated that Au/Cu ferrite oxide-polymer core–shell nanoreactor is a potential agent for chemodynamic/photodynamic synergetic therapy.

Synthesis of Bromo Aniline derivatives and an insilico approach against HSP90 chaperone

Heterocyclic compounds are occupied in a huge variety of drugs which are widely distributed in nature and essential to life; Aniline has its remarkable influence in products that have been used by humans in day to day life. Its derivatives have made a remarkable trend over drug synthesis and this work shows the synthesis, characterization of some Bromo aniline derivatives and their action against the insilico docking studies against 4,5 Diaryl Isoxazole Hsp90 Chaperone Inhibitors a potential skin cancer therapeutic agent (2VCJ).

Tumor Microenvironment-Responsive Yolk–Shell NaCl@Virus-Inspired Tetrasulfide-Organosilica for Ion-Interference Therapy via Osmolarity Surge and Oxidative Stress Amplification

Ion-interference therapy, which utilizes ions to disturb intracellular biological processes, provides inspiration for tumor therapy. Artificially reversing osmotic pressure by transporting large amounts of physiological ions to tumor cells is a straightforward yet low-toxic strategy for ion-interference therapy. However, it is hard to achieve due to the serious limitations of single-ion delivery. Herein, we skillfully deliver NaCl nanocrystals to tumor sites and sequentially realize the explosive release of Na+/Cl- inside tumor cells by utilizing a virus-mimicking and glutathione (GSH)-responsive hollow mesoporous tetrasulfide-bridged organosilica (ssss-VHMS). Once the ssss-VHMS-wrapped NaCl nanocrystals (NaCl@ssss-VHMS) accumulate in the tumors, they would rapidly invade tumor cells via spike surface-assisted endocytosis, thus bypassing Na+/K+-ATPase transmembrane ion transporters. Afterward, the intracellular overproduced GSH of tumor cells would trigger the rapid degradation of ssss-VHMS via thiol-tetrasulfide exchange, which could not only remarkably deplete the GSH but also explosively release the Na+/Cl-, leading to the osmolarity surge accompanied by reactive oxygen species (ROS) generation. The cell swelling, ROS storm, and GSH exhaustion of NaCl@ssss-VHMS effectively eradicated tumor cells by caspase-1-dependent pyroptosis, caspase-3-dependent apoptosis, and GPX4-dependent ferroptosis, respectively, thus synergistically inhibiting tumor growth. We believe that NaCl@ssss-VHMS would be a potential cancer therapeutic agent, and this discovery could provide a perspective for exploring synergistic ion-interference therapy.

Computational study, synthesis and evaluation of active peptides derived from Parasporin-2 and spike protein from Alphacoronavirus against colorectal cancer cells.

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and β-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.

Biosynthesized Silver Nanoparticles for Cancer Therapy and In Vivo Bioimaging.

Simple SummaryChemotherapy, a conventional treatment strategy, is associated with several limitations. Alternatively, cancer nanotechnology offers new strategies for remedy from drug delivery and extending to therapeutics using nanoformulation. Recently, silver nanoparticles were utilized for different cancer theranostics. In this context, the current manuscript demonstrates the design and development of biologically synthesized silver nanoparticles (AgZE) and their applications for cancer theranostics. The synthesized AgZE is optimized and thoroughly characterized. The AgZE exhibits biocompatibility and selective anticancer activity towards the cancer cell lines established through various assays. The fluorescence properties of AgZE are observed in the NIR region (excitation: 710 nm, emission: 820 nm) in the normal and tumor bearing C57BL6/J mice. The silver of AgZE is found to be biodistributed in different vital organs as analyzed by ICPOES. Thereafter, these results highlight that AgZE could be an efficient cancer therapeutic and NIR based non-invasive imaging agent in the upcoming times.In the current communication, a simple, environmentally compatible, non-toxic green chemistry process is used for the development of silver nanoparticles (AgZE) by the reaction between silver nitrate (AgNO3) and the ethanolic leaf extract of Zinnia elegans (ZE). The optimization of AgZE is carried out using a series of experiments. Various physico-chemical techniques are utilized to characterize the nanomaterials. The cell viability assay of AgZE in normal cells (CHO, HEK-293T, EA.hy926, and H9c2) shows their biocompatible nature, which is supported by hemolytic assay using mouse RBC. Interestingly, the nanoparticles exhibited cytotoxicity towards different cancer cell lines (U-87, MCF-7, HeLa, PANC-1 and B16F10). The detailed anticancer activity of AgZE on human glioblastoma cell line (U-87) is exhibited through various in vitro assays. In vivo the AgZE illustrates anticancer activity by inhibiting blood vessel formation through CAM assay. Furthermore, the AgZE nanoparticles when intraperitoneally injected in C57BL6/J mice (with and without tumor) exhibit fluorescence properties in the NIR region (excitation: 710 nm, emission: 820 nm) evidenced by bioimaging studies. The AgZE biodistribution through ICPOES analysis illustrates the presence of silver in different vital organs. Considering all the results, AgZE could be useful as a potential cancer therapeutic agent, as well as an NIR based non-invasive imaging tool in near future.

Aloe-emodin inhibits the proliferation, migration, and invasion of melanoma cells via inactivation of the Wnt/beta-catenin signaling pathway

BackgroundAloe-emodin is reported as a potential cancer therapeutic agent due to its inhibition of the proliferation, migration, and invasion of cancer cells. This study aimed to confirm the effects of aloe-emodin on the progression of melanoma and identify the underlying molecular mechanisms.MethodsThe effects of aloe-emodin treatment (concentrations ranging from 0 to 25 µg, 48 h) on proliferation, apoptosis, distribution of cell cycle, migration, and invasion were detected by performing Cell Counting Kit-8 (CCK-8) assay, colony formation assay, flow cytometry, wound healing assay, and Transwell invasion experiments. Rescue experiments were carried out by overexpression of β-catenin to verify the role of β-catenin in the inhibition of melanoma by aloe-emodin. The analysis was carried out at the animal level by constructing tumor-bearing nude mice model.ResultsThe results showed that aloe-emodin prominently reduced the proliferation, migration, and invasion of melanoma cells. Additionally, it was found that aloe-emodin significantly enhanced the cell apoptosis and induced G2 phase arrest of melanoma cells via enhancing the expressions of cleaved-caspase3, bax, and reducing cyclinD1, c-myc, and bcl-2. In addition, aloe-emodin could also inhibit Wnt3a levels, and promote GSK3-beta and beta-catenin phosphorylation. In vivo experiments also showed that overexpression of beta-catenin reversed the effects of aloe-emodin on tumor growth.ConclusionsIn conclusion, our findings indicated that aloe-emodin might prominently inhibit the tumor growth and metastasis of melanoma via the Wnt/beta-catenin signaling pathway in vitro. Therefore, aloe-emodin may serve as a potential drug for the clinical treatment of melanoma.

Anti-cancer effects of lucidadiol against malignant melanoma cells

Melanoma is one of the most aggressive and lethal skin cancers. Lucidadiol is a triterpenoid isolated from Ganoderma lucidum and is known to have various biological functions, including antibacterial effects. However, the anti-cancer effects and mechanism of action of lucidadiol in malignant melanoma are unknown. In this study, lucidadiol significantly reduced B16 melanoma cell viability in a dose- and time-dependent manner. In addition, lucidadiol induced apoptosis and suppressed cell mobility in B16 melanoma cells. Moreover, our findings revealed that lucidadiol remarkably downregulated phospho-Akt/ERK/JNK, but not p38. Taken together, our results suggest that lucidadiol could exerts its anti-cancer effects by inducing apoptosis via modulation of the Akt/MAPK pathway. Therefore, lucidadiol may be a potential cancer therapeutic agent for malignant melanoma.

Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells.

Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty, and are an important source for innovative drugs and lead compounds. We present herein that natural product santamarine targeted thioredoxin reductase (TrxR) to weaken its antioxidative function in cells, accompanied by accumulation of high levels of reactive oxygen species (ROS), and finally induced a new mechanism of tumor cell oxidative stress-mediated apoptosis. TrxR knockdown or overexpression cell lines were employed to further evaluate the cytotoxicity of santamarine regulated by TrxR, demonstrated that TrxR played a key role in the physiological effect of santamarine on cells. Santamarine targeting TrxR reveals its previously unrecognized mechanism of antitumor and provides a basis for the further development of santamarine as a potential cancer therapeutic agent.

Construction and antitumor activity of selenium nanoparticles decorated with the polysaccharide extracted from Citrus limon (L.) Burm. f. (Rutaceae)

Selenium nanoparticles (SeNPs), a potential cancer therapeutic agent, have attracted widespread attention owing to their high bioavailability and remarkable anticancer activity. Nevertheless, the poor water solubility and dispersibility of SeNPs seriously limit their applications. In the present study, we synthesized stable and individual spherical selenium nanoparticles (CL90-Tw-SeNP2) with an average diameter of approximately 79 nm using a polysaccharide extracted from Citrus limon (CL90) and Tween-80 as the decorator and stabilizers. The proportion of selenium in CL90-Tw-SeNP2 was 10.6%. CL90-Tw-SeNP2 possessed high stability and good dispersion in water for more than three months. The subsequent biological assay revealed that CL90-Tw-SeNP2 showed remarkable antitumor effects against HepG2 cells, with an IC50 value of 49.13 μg/mL, by inducing cell apoptosis. Furthermore, an in vivo zebrafish assay to explore possible applications indicated that CL90-Tw-SeNP2 could inhibit the proliferation and migration of tumors and the zebrafish angiogenesis. These results indicated that CL90-Tw-SeNP2 could be a potential agent for cancer treatment, especially against human liver hepatoma cancer.

Abstract 977: Mcl-1 levels critically determines the sensitivities of human colon cancer cells to APG1244, a novel Bcl-2 and Bcl-XLinhibitor, that induces Bax- and caspase-8- dependent apoptosis

Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide due to its poor prognosis. Most of the patients receive surgical resection when diagnosed as CRC, whereas the recurrence rate is very high. Therefore, additional treatment options, such as targeted therapy, are still urgently needed. The novel BH3 mimetic, APG1244 (a prodrug for APG1252), is a highly potent Bcl-2 and Bcl-XL dual inhibitor and being tested in clinical trials as a potential cancer therapeutic agent. The current study focuses on demonstrating the therapeutic efficacies of APG1244 against colorectal cancer and understanding the underlying mechanisms. A panel of CRC cell lines with different levels of Bcl-2, Bcl-XL and Mcl-1 possessed different sensitivities to APG1244. APG1244 effectively decreased the survival of CRC cell lines, particularly those expressing relative low levels of Mcl-1, with induction of apoptosis. High levels of Mcl-1 in these cell lines were significantly correlated to decreased sensitivity to APG1244. APG1244, when combined with a Mcl-1 inhibitor, synergistically decreased the survival and induced apoptosis of APG1244-insensitive cell lines with high levels of Mcl-1. This combination could further decreased the survival and enhanced apoptosis even in the cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG1244's effects on decreasing cell survival and inducing apoptosis, which can be reversed by Mcl-1 inhibition. In our study, it appears that APG1244 quickly activated caspase-8 and caspase-3 and induced PARP cleavage with induction of cytochrome C and Smac release from mitochondria. Deficiency of Bax, Smac, Bim or PUMA, but not FADD, in CRC cells protected (BAX-KO) or partially protected cells from APG1244-induced apoptosis, indicating that APG1244 induces Bax-dependent apoptosis. Furthermore, blockage of caspase-8 with a caspase-8 specific inhibitor abolished cleavage of caspase-3 and PARP including attenuation of cytochrome C and Smac release induced by APG1244, suggesting a caspase-8-dependent mechanism. The current study thus demonstrates the potential of APG1244 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with a Mcl-1 inhibitor for CRC treatment, warranting further evaluation in vivo and in the clinic. Citation Format: Weilong Yao, Shi-Yong Sun. Mcl-1 levels critically determines the sensitivities of human colon cancer cells to APG1244, a novel Bcl-2 and Bcl-XLinhibitor, that induces Bax- and caspase-8- dependent apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 977.

White Button Mushroom Disrupts AR Signaling in Prostate Cancer: The Scientific Basis for a Diet-Based Chemoprevention

Abstract White button mushroom (WBM) (Agaricus bisporus) is a potential prostate cancer (PCa) chemo-preventive and therapeutic agent. Our clinical phase trial of WBM powder in patients with biochemically recurrent PCa indicated that WBM intake reduced the circulating levels of prostate-specific antigen (PSA), with minimal side effects [1]. We hypothesized that WBM exerts its effects on PCa through the androgen receptor (AR) signaling axis. We thus conducted the reverse translational study. Androgen-sensitive PCa cell lines (LNCaP and VCaP) and patient-derived-xenografts (PDX), of a prostate tumor (TM00298) were used. In both LNCaP and VCaP cells, western blots and qRT-PCR assays indicated that WBM extract (6~30 mg/mL) suppressed DHT-induced PSA expression and cell proliferation in a dose-dependent manner. Immunofluorescence on AR revealed that the nuclear localization of AR was reduced upon WBM extract treatment, which agreed with the results of a PSA promotor-luciferase assay, suggesting that WBM extract inhibited DHT-induced luciferase activity. RNA-Seq on WBM-treated LNCaP cells confirmed that WBM treatment suppressed androgen response pathways and cell-cycle control pathways. Our prostate cancer PDX showed that oral intake of WBM extract (200 mg/kg/day) significantly suppressed tumor growth, as well as decreased PSA levels in both tumors and serum. Both in vitro and in vivo studies suggested that chemical(s) in WBM extract behave as AR antagonist(s). We previously identified a conjugated linoleic acid isomer (CLA-9Z11E) as an active component in WBM extract. In the present study, we extended these findings by performing LanthaScreen™ TR-FRET AR Coactivator Interaction Assays for a direct interaction of CLA-9Z11E with AR. We report here that CLA-9Z11E exerts a strong antagonist potency against the recruitment of an AR coactivator peptide towards AR. The inhibitory effect of CLA-9Z11E (IC50: 350 nM) was nearly two times stronger than the known AR antagonist, cyproterone acetate (IC50: 672 nM). The information gained from this study improves the overall understanding of how WBM may contribute to the prevention and treatment of PCa. It also serves as an important, scientific basis for developing diet-based chemoprevention and integrative therapeutic strategies for prostate cancer (supported by NIH R01 CA227230). Reference: [1] Twardowski P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer. 2015.121(17):2942-50.