Conventional Anticancer Drugs Research Articles

Innovative Delivery and Release Systems for Antioxidants and Other Active Substances in the Treatment of Cancer.

Cancer is one of the major diseases leading to death worldwide, and the fight against the disease is still challenging. Cancer diseases are usually associated with increased oxidative stress and the accumulation of reactive oxygen and nitrogen species as a result of metabolic alterations or signaling aberrations. While numerous antioxidants exhibit potential therapeutic properties, their clinical efficiency against cancer is limited and even unproven. Conventional anticancer antioxidants and drugs have, among others, the great disadvantage of low bioavailability, poor targeting efficiency, and serious side effects, constraining their use in the fight against diseases. Here, we review the rationale for and recent advances in potential delivery systems that could eventually be employed in clinical research on antioxidant therapy in cancer. We also review some of the various strategies aimed at enhancing the solubility of poorly water-soluble active drugs, including engineered delivery systems such as lipid-based, polymeric, and inorganic formulations. The use of cyclodextrins, micro- and nanoemulsions, and thermosensitive smart liposomes as useful systems for the delivery and release of poorly aqueous-soluble drugs, improving their bioactivity and stability, is also addressed. We also provide some details on their formulation processes and their use in a variety of medical applications. Finally, we briefly cover a case study specifically focused on the use of delivery systems to minimize oral cancer and associated dental problems.

Icariin as a potential anticancer agent: a review of its biological effects on various cancers.

Numerous chemical compounds used in cancer treatment have been isolated from natural herbs to address the ever-increasing cancer incidence worldwide. Therein is icariin, which has been extensively studied for its therapeutic potential due to its anti-inflammatory, antioxidant, antidepressant, and aphrodisiac properties. However, there is a lack of comprehensive and detailed review of studies on icariin in cancer treatment. Given this, this study reviews and examines the relevant literature on the chemopreventive and therapeutic potentials of icariin in cancer treatment and describes its mechanism of action. The review shows that icariin has the property of inhibiting cancer progression and reversing drug resistance. Therefore, icariin may be a valuable potential agent for the prevention and treatment of various cancers due to its natural origin, safety, and low cost compared to conventional anticancer drugs, while further research on this natural agent is needed.

Potential from synergistic effect of quercetin and paclitaxel co-encapsulated in the targeted folic–gelatin–pluronic P123 nanogels for chemotherapy

Dual-drug delivery systems for anticancer therapy have recently attracted substantial attention due to their potency to overcome limitations of conventional anti-cancer drugs, tackle drug resistance problems, as well as improve the therapeutic efficacy. In this study, we introduced a novel nanogel based on folic acid-gelatin-pluronic P123 (FA-GP-P123) conjugate to simultaneously deliver quercetin (QU) and paclitaxel (PTX) to the targeted tumor. The results indicated that the drug loading capacity of FA-GP-P123 nanogels was significantly higher than that of P123 micelles. The kinetic release profiles of QU and PTX from the nanocarriers were governed by Fickian diffusion and swelling behavior, respectively. Notably, FA-GP-P123/QU/PTX dual-drug delivery system induced higher toxicity to MCF-7 and Hela cancer cells than either QU or PTX individual delivery system, and the non-targeted dug delivery system (GP-P123/QU/PTX), indicating the synergistic combination of dual drugs and FA positive targeting effect. Furthermore, FA-GP-P123 could effectively deliver QU and PTX to tumors in vivo after administration into MCF-7 tumor-bearing mice, which resulted in 94.20 ± 5.90 % of tumor volume reduced at day 14. Moreover, the side effects of the dual-drug delivery system were significantly reduced. Overall, we suggest FA-GP-P123 as potential nanocarrier for dual-drug delivery for targeted chemotherapy.

Targeting pre-mRNA splicing in cancers: roles, inhibitors, and therapeutic opportunities.

Accumulating evidence has indicated that pre-mRNA splicing plays critical roles in a variety of physiological processes, including development of multiple diseases. In particular, alternative splicing is profoundly involved in cancer progression through abnormal expression or mutation of splicing factors. Small-molecule splicing modulators have recently attracted considerable attention as a novel class of cancer therapeutics, and several splicing modulators are currently being developed for the treatment of patients with various cancers and are in the clinical trial stage. Novel molecular mechanisms modulating alternative splicing have proven to be effective for treating cancer cells resistant to conventional anticancer drugs. Furthermore, molecular mechanism-based combination strategies and patient stratification strategies for cancer treatment targeting pre-mRNA splicing must be considered for cancer therapy in the future. This review summarizes recent progress in the relationship between druggable splicing-related molecules and cancer, highlights small-molecule splicing modulators, and discusses future perspectives of splicing modulation for personalized and combination therapies in cancer treatment.

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation.

Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin (3f) was the most promising compound with a PC50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f, demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.

The Assessment of Calcium and Bleomycin Cytotoxic Efficiency in Relation to Cavitation Dosimetry.

Microbubble (MB)- and ultrasound (US)-facilitated intracellular Ca2+ delivery, known as sonoporation (SP), is a promising anticancer treatment modality, since it allows a spatio-temporally controllable and side-effect-free alternative to conventional chemotherapy. The current study provides extensive evidence that a 5 mM concentration of Ca2+ in combination with US alone or US and Sonovue MBs can be an alternative to the conventional 20 nM concentration of the anticancer drug bleomycin (BLM). Ca2+ application together with SP induces a similar level of death in Chinese hamster ovary cells to the combination of BLM and SP but does not cause systemic toxicity, as is inherent to conventional anticancer drugs. In addition, Ca2+ delivery via SP alters three vital characteristics essential for viable cells: membrane permeability, metabolic activity and proliferation ability. Most importantly, Ca2+ delivery via SP elicits sudden cell death-occurring within 15 min-which remains similar during 24-72 h and 6 d periods. The extensive study of US waves side-scattered by MBs led to the quantification of the cavitation dose (CD) separately for subharmonics, ultraharmonics, harmonics and broadband noise (up to 4 MHz). The CD was suitable for the prognostication of the cytotoxic efficiency of both anticancer agents, Ca2+ and BLM, as was indicated by an overall high (R2 ≥ 0.8) correlation (22 pairs in total). These extensive analytical data imply that a broad range of frequencies are applicable for the feedback-loop control of the process of US-mediated Ca2+ or BLM delivery, successively leading to the eventual standardization of the protocols for the sonotransfer of anticancer agents as well as the establishment of a universal cavitation dosimetry model.

GSK-J4: An H3K27 histone demethylase inhibitor, as a potential anti-cancer agent.

Aberrant epigenetic modifications are emerging as potent drivers of tumor initiation and progression. The deregulation of H3K27me3 marks has shown to play an important role in cancer progression in several cancers. The H3K27me3 mark is associated with gene silencing. The reversible nature of these epigenetic aberrations makes them an important target for treating cancer. GSK-J4 is a histone demethylase inhibitor that inhibits the JMJD3/UTX enzyme, which results in the upregulation of H3K27me3 levels. In this review, the anti-cancer properties of GSK-J4 have been summarized, the various molecular pathways targeted, in-vivo studies, and drug combination studies in different cancer models. GSK-J4 targeted pathways like apoptosis, cell cycle, invasion, migration, DNA damage repair, metabolism, oxidative stress, stemness, etc. GSK-J4 is a promising candidate alone and in combination with other conventional anti-cancer drugs against different cancer types.

Abstract 6787: Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy

Abstract While oncolytic virotherapy has shown promising results for uncured patients with cancer, its effects on lung cancer remain unclear. Lung cancer is mostly unlikely to respond to conventional anticancer drug, therefore, oncolytic virotherapy can be the best option. Herein, we evaluated the anti-cancer activity of the previously developed three oncolytic vaccinia viruses encoding TNF-related apoptosis-inducing ligand (TRAIL), angiopoietin 1 (Ang1) and both genes, especially on killing lung cancer (LC). In this study, we confirmed that our engineered vaccinia viruses showed overall higher anti-cancer activity on lung cancer cells, compared to WT. Vaccinia virus engineered with both Ang1 and TRAIL (vTRAN) showed the highest oncolytic activity and selectivity in vitro (WT < vTRAIL < vAng1 < vTRAN). However, In vivo LLC1 murine lung cancer syngeneic model showed highest attenuated tumor growth when vTRAIL was treated (WT < vAng1 < vTRAN < vTRAIL), which was in accordance with CD8 high PD1 low expression levels in the tissues. It concludes that engineered vaccinia virus harboring TRAIL (vTRAIL) is the promising therapeutic option for in vivo lung cancer therapy. Citation Format: So Young Yoo. Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6787.

Establishing the applicability of cancer vaccines in combination with chemotherapeutic entities: current aspect and achievable prospects.

Cancer immunotherapy is one of the recently developed cancer treatment modalities. When compared with conventional anticancer drug regimens, immunotherapy has shown significantly better outcomes in terms of quality of life and overall survival. It incorporates a wide range of immunomodulatory modalities that channel the effects of the immune system either by broadly modulating the host immune system or by accurately targeting distinct tumor antigens. One such treatment modality that has gained interest is cancer vaccine therapy which acts by developing antibodies against tumor cells. Cancer vaccines target individual peptides or groups of antigens that are released by tumor cells and presented by the APCs. This also initiates an effective process to activate the host immune responses. Studies on various types of cancer vaccines are conducted, out of which only few are approved by FDA for clinical uses. Despite of documented safety and efficacy of conventional chemotherapy and cancer vaccines, individually they did not produce substantial results in eradication of the cancer as a monotherapy. Hence, the combination approach holds the extensive potential to provide significant improvement in disease outcomes. Certain chemotherapy has immunomodulatory effects and is proven to synergize with cancer vaccines thereby enhancing their anti-tumor activities. Chemotherapeutic agents are known to have immunostimulatory mechanisms apart from its cytotoxic effect and intensify the anti-tumor activities of vaccines by various mechanisms. This review highlights various cancer vaccines, their mechanism, and how their activity gets affected by chemotherapeutic agents. It also aims at summarizing the evidence-based outcome of the combination approach of a cancer vaccine with chemotherapy and a brief on future aspects.

Abstract 2843: RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells

Abstract Overcoming ATP-binding cassette subfamily G member 2 (ABCG2)-mediated multidrug resistance (MDR) has attracted the attention of scientists because one of the critical factors leading to MDR is the overexpression of ABCG2. Identification of novel chemotherapeutic reagents as inhibitors of ABCG2 has been considered an effective strategy. RN486, a Bruton’s Tyrosine Kinase (BTK) inhibitor, was discovered to potentially reverse ABCB1-mediated MDR. In this study, we reported that RN486 effectively antagonizes ABCG2-mediated MDR in cancer cells. Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. The reversal mechanistic studies showed that RN486 increased the accumulation and decreased the efflux of ABCG2 substrate drug in ABCG2-overexpressing cancer cells. In addition, the inhibitory effect of RN486 on ABCG2-associated ATPase activity was also verified. Docking analysis indicated a strong binding between RN486 and ABCG2 transporter. Meanwhile, the AGCG2 subcellular localization and expression level were not altered by the treatment of RN486. Taken together, our studies suggest that RN486 can antagonize ABCG2-mediated MDR in cancer cells via interacting with ABCG2 and inhibiting the transporting function. RN486 could be potentially used in combination with chemotherapy against ABCG2-mediated MDR in cancers. Citation Format: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen. RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2843.

Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles

Conventional anti-cancer drugs, including doxorubicin, are associated with high toxicity and non-specific distribution in the body which results in a cascade of side effects. Cancer cells can utilize autophagy to promote tolerance to the stress induced by anti-cancer agents; this may be the major cause of drug resistance in advanced tumors. Owing to the molecular dynamism of cancer cells, targeting the pro-apoptotic survival pathways such as autophagy may increase the effectiveness of existing therapeutic agents at lower concentrations, thereby reducing the side effects of such agents. SAR405 is an inhibitor of autophagy activity due to its molecular interactions within the ATP binding site; however, it suffers from extracellular premature degradation and poor cellular uptake. Conversely, chitosan nanoparticles are considered biologically degradable, non-toxic, and biocompatible drug delivery agents that can be used to minimize the side effects of conventional therapeutic agents whilst increasing their intracellular uptake. In this study, a binary therapeutic strategy for the enhancement of the efficacy of doxorubicin while simultaneously inhibiting autophagy via a nano-mediated delivery system is reported. Autophagic inhibition was achieved via the improvement of SAR405 cellular uptake using SAR405-loaded chitosan nanoparticles. The synthesized nanoparticles were subsequently characterized for parameters of hydrodynamic diameter and polydispersity, while encapsulation and drug loading efficiencies were determined. Morphological characterization of the nanoparticles was elucidated using electron microscopy, and the cytotoxicity of the SAR405-loaded chitosan nanoparticles in combination treatments with doxorubicin was assessed through MTT and Annexin-v apoptosis assays. Autophagy progression through autophagosome formation was also evaluated using CYTO-ID staining. Following encapsulation, the size of the SAR405-loaded chitosan nanoparticles significantly increased from 54 nm to 161 nm at 10 µM SAR405 concentration, while the polydispersity index increased from 0.11 to 0.31 denoting presence of both encapsulated and unencapsulated moieties. When A549 lung cancer cells were treated with the IC50 values of doxorubicin in combination with SAR405-encapsulated CNP, an approximately 47% more reduction in cell viability was observed via the Annexin V-FITC/PI assay compared to using doxorubicin alone. Inhibition of autophagy was also detected in cells treated with SAR405 delivered using the nanoparticle system and was thought to be the primary reason towards a decrease in the resistance of the cancer cells to doxorubicin and thus increased its efficacy at lower concentrations. Therefore, this study has demonstrated a potential way of targeting cancer cell survival pathways that can be considered an effective way of increasing the efficacy of chemotherapeutic drugs.

Codelivery of Phytochemicals with Conventional Anticancer Drugs in Form of Nanocarriers.

Anticancer drugs in monotherapy are ineffective to treat various kinds of cancer due to the heterogeneous nature of cancer. Moreover, available anticancer drugs possessed various hurdles, such as drug resistance, insensitivity of cancer cells to drugs, adverse effects and patient inconveniences. Hence, plant-based phytochemicals could be a better substitute for conventional chemotherapy for treatment of cancer due to various properties: lesser adverse effects, action via multiple pathways, economical, etc. Various preclinical studies have demonstrated that a combination of phytochemicals with conventional anticancer drugs is more efficacious than phytochemicals individually to treat cancer because plant-derived compounds have lower anticancer efficacy than conventional anticancer drugs. Moreover, phytochemicals suffer from poor aqueous solubility and reduced bioavailability, which must be resolved for efficacious treatment of cancer. Therefore, nanotechnology-based novel carriers are employed for codelivery of phytochemicals and conventional anticancer drugs for better treatment of cancer. These novel carriers include nanoemulsion, nanosuspension, nanostructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, dendrimers, metallic nanoparticles, carbon nanotubes that provide various benefits of improved solubility, reduced adverse effects, higher efficacy, reduced dose, improved dosing frequency, reduced drug resistance, improved bioavailability and higher patient compliance. This review summarizes various phytochemicals employed in treatment of cancer, combination therapy of phytochemicals with anticancer drugs and various nanotechnology-based carriers to deliver the combination therapy in treatment of cancer.

Combination of Copper Metallodendrimers with Conventional Antitumor Drugs to Combat Cancer in In Vitro Models.

Copper carbosilane metallodendrimers containing chloride ligands and nitrate ligands were mixed with commercially available conventional anticancer drugs, doxorubicin, methotrexate and 5-fluorouracil, for a possible therapeutic system. To verify the hypothesis that copper metallodendrimers can form conjugates with anticancer drugs, their complexes were biophysically characterized using zeta potential and zeta size methods. Next, to confirm the existence of a synergetic effect of dendrimers and drugs, in vitro studies were performed. The combination therapy has been applied in two cancer cell lines: MCF-7 (human breast cancer cell line) and HepG2 (human liver carcinoma cell line). The doxorubicin (DOX), methotrexate (MTX) and 5-fluorouracil (5-FU) were more effective against cancer cells when conjugated with copper metallodendrimers. Such combination significantly decreased cancer cell viability when compared to noncomplexed drugs or dendrimers. The incubation of cells with drug/dendrimer complexes resulted in the increase of the reactive oxygen species (ROS) levels and the depolarization of mitochondrial membranes. Copper ions present in the dendrimer structures enhanced the anticancer properties of the whole nanosystem and improved drug effects, inducing both the apoptosis and necrosis of MCF-7 (human breast cancer cell line) and HepG2 (human liver carcinoma cell line) cancer cells.

Phytofabrication and Characterisation of Zinc Oxide Nanoparticles Using Pure Curcumin.

Zinc oxide and curcumin, on their own and in combination, have the potential as alternatives to conventional anticancer drugs. In this work, zinc oxide nanoparticles (ZnO NPs) were prepared by an eco-friendly method using pure curcumin, and their physicochemical properties were characterised. ATR-FTIR spectra confirmed the role of curcumin in synthesising zinc oxide curcumin nanoparticles (Green-ZnO-NPs). These nanoparticles exhibited a hexagonal wurtzite structure with a size and zeta potential of 27.61 ± 5.18 nm and -16.90 ± 0.26 mV, respectively. Green-ZnO-NPs showed good activity towards studied bacterial strains, including Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. The minimum inhibitory concentration of Green-ZnO-NPs was consistently larger than that of chemically synthesised ZnO NPs (Std-ZnO-NPs) or mere curcumin, advocating an additive effect between the zinc oxide and curcumin. Green-ZnO-NPs demonstrated an efficient inhibitory effect towards MCF-7 cells with IC50 (20.53 ± 5.12 μg/mL) that was significantly lower compared to that of Std-ZnO-NPs (27.08 ± 0.91 μg/mL) after 48 h of treatment. When Green-ZnO-NPs were tested against Artemia larvae, a minimised cytotoxic effect was observed, with LC50 being almost three times lower compared to that of Std-ZnO-NPs (11.96 ± 1.89 μg/mL and 34.60 ± 9.45 μg/mL, respectively). This demonstrates that Green-ZnO-NPs can be a potent, additively enhanced combination delivery/therapeutic agent with the potential for anticancer therapy.

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes.

Canine malignant lymphoma is a common neoplasia in dogs, and some studies have used dogs as a research model for molecular mechanisms of lymphomas in humans. In two species, chemotherapy is the treatment of choice, but the resistance to conventional anticancer drugs is frequent. The knowledge of molecular mechanisms of development and progression of neoplasia has expanded in recent years, and the underlying epigenetic mechanisms are increasingly well known. These studies open up new ways of discovering therapeutic biomarkers. Histone deacetylases and demethylase inhibitors could be a future treatment for canine lymphoma, and the use of microRNAs as diagnosis and prognosis biomarkers is getting closer. This review summarises the epigenetic mechanisms underlying canine lymphoma and their possible application as treatment and biomarkers, both prognostic and diagnostic.

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Acoustically-Activated Liposomal Nanocarriers to Mitigate the Side Effects of Conventional Chemotherapy with a Focus on Emulsion-Liposomes.

To improve currently available cancer treatments, nanomaterials are employed as smart drug delivery vehicles that can be engineered to locally target cancer cells and respond to stimuli. Nanocarriers can entrap chemotherapeutic drugs and deliver them to the diseased site, reducing the side effects associated with the systemic administration of conventional anticancer drugs. Upon accumulation in the tumor cells, the nanocarriers need to be potentiated to release their therapeutic cargo. Stimulation can be through endogenous or exogenous modalities, such as temperature, electromagnetic irradiation, ultrasound (US), pH, or enzymes. This review discusses the acoustic stimulation of different sonosensitive liposomal formulations. Emulsion liposomes, or eLiposomes, are liposomes encapsulating phase-changing nanoemulsion droplets, which promote acoustic droplet vaporization (ADV) upon sonication. This gives eLiposomes the advantage of delivering the encapsulated drug at low intensities and short exposure times relative to liposomes. Other formulations integrating microbubbles and nanobubbles are also discussed.

Intracellular Glucose-Depriving Polymer Micelles for Antiglycolytic Cancer Treatment.

A new anticancer strategy to exploit abnormal metabolism of cancer cells rather than to merely control the drug release or rearrange the tumor microenvironment is reported. An antiglycolytic amphiphilic polymer, designed considering the unique metabolism of cancer cells (Warburg effect) and aimed at the regulation of glucose metabolism, is synthesized through chemical conjugation between glycol chitosan (GC) and phenylboronic acid (PBA). GC-PBA derivatives form stable micellar structures under physiological conditions and respond to changes in glucose concentration. Once the micelles accumulate at the tumor site, intracellular glucose capture occurs, and the resultant energy deprivation through the inhibition of aerobic glycolysis remarkably suppresses tumor growth without significant side effects in vivo. This strategy highlights the need to develop safe and effective cancer treatment without the use of conventional anticancer drugs.

Anticancer effects of the HDAC inhibitor, 3β,6β‑dihydroxyurs‑12‑en‑27‑oic acid, in MCF‑7 breast cancer cells via the inhibition of Akt/mTOR pathways.

Astilbechinensis (A.chinensis) is a perennial herb that is used to treat chronic bronchitis and pain. The anticancer activity of 3β,6β‑dihydroxyurs‑12‑en‑27‑oic acid (ACT‑3), a major component isolated from A.chinensis, has not yet been investigated in detail. The purpose of the present study was to investigate the histone deacetylase (HDAC) inhibitory and anticancer activities of ACT‑3 compared with suberoylanilide hydroxamic acid (SAHA) in MCF‑7 human breast cancer cells. The purity of ACT‑3 was determined using high‑performance liquid chromatography. In the present study, the effects of ACT‑3 on anticancer effects of MCF‑7 cells were determined by measuring the level of apoptotic cell death and cell cycle regulator using flow cytometry analysis and western blot analysis, respectively. The effects of ACT‑3 on HDAC enzyme activity were measured using assay kits. ACT‑3 and SAHA increased the levels of acetylated histone H3 and reduced the levels of HDAC1 and HDAC3 in MCF‑7 cells. ACT‑3 significantly decreased the cell viability in a concentration‑dependent manner and induced different morphological changes at high concentrations. ACT‑3 and SAHA significantly inhibited the colony formation in MCF‑7 cells. ACT‑3 inhibited total HDAC activity in a dose‑dependent manner. ACT‑3 significantly reduced the expression levels of cyclin D1 and cyclin‑dependent kinase 4, and upregulated the expression levels of p21WAF1 and p53. A significant increase in the G1 phase cell population was observed in MCF‑7 cells and ACT‑3 induced apoptosis by reducing the ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2‑associated X (Bax) and releasing cleaved caspase 9. Additionally, ACT‑3 significantly increased autophagic cell death by inhibiting the serine‑threonine kinase/mammalian target of the rapamycin pathway. Autophagy induction was confirmed via acridine orange staining. ACT‑3 significantly increased the pERK1/2 and p21 in MCF‑7 cells. Thus, the activated ERK pathway played an important role in cell cycle arrest and apoptosis via ERK‑dependent induction of p21 in MCF‑7 cells. These data indicated that ACT‑3 can be used as a promising anticancer agent to overcome the limitations and reduce the side effects of conventional anticancer drugs.

Chemical screening identifies the anticancer properties of Polyporous tuberaster.

Most conventional anticancer drugs cause resistance to chemotherapy, which has emerged as one of the major obstacles to cancer treatment. In order to address this issue, efforts have been made to select new anticancer compounds from natural sources. The aim of this study is to identify novel anticancer compounds from mycelial culture extracts belonging to Polyporus tuberaster (P. tuberaster). Here, we found that mycelial culture extracts of P. tuberaster cultured in PDB medium (pt-PDB) effectively inhibited cancer cell growth. pt-PDB reduced the growth of cancer cells through apoptosis induction and S-phase arrest. The anticancer efficacy of pt-PDB was not to limited to one type of cancer. Furthermore, unlike traditional anticancer medications, pt-PDB did not increase the proportion of side population (SP) cells, which plays a key role in the development of chemoresistance. Taken together, we discovered a novel anticancer drug candidate that has anticancer properties without increasing the proportion of SP cells. This new drug candidate can be used for the treatment of cancer, especially chemoresistant malignancies, and will provide a breakthrough in the treatment of chemoresistant cancer.