Inhibited Cancer Cell Viability Research Articles

Synthesis and physico-chemical investigation of thiolated dextran derivative: Design and application of a redox-responsive drug delivery system.

In the present investigation, redox-responsive-based dextran carriers were developed for the controlled release of hydrophobic molecules via a reducing agent naturally present in cells, namely glutathione. In this sense, dextran was modified with a thiol derivative. The roles of the hydrophilic segments in the molecular self-organisation of polysaccharide derivatives into nanoparticles were investigated by varying the average dextran molar mass. Crosslinked thiolated dextran particles were good carriers of hydrophobic molecules such as Nile red dye, which were efficiently encapsulated in the hydrophobic core and then selectively released. Indeed, the disulfide linkage connecting the hydrophobic tail with dextran was found to be cleaved by glutathione under physiological conditions for the fast release of Nile red. The cytotoxicity of the dextran-based particles was examined, and it was found to be nontoxic to living cells. Finally, we explored the versatility of dextran-derived particle drug carriers for pancreatic cancer treatment. The designed carriers were loaded with the anticancer drug paclitaxel and the obtained particles exhibited redox-responsive drug release and excellent anticancer activities with up to 90% inhibition of cancer cell viability. Thus, the developed dextran derivatives are highly promising and suitable for a wide range of biomedical applications that require the loading and release of hydrophobic compounds.

Charge reversible hyaluronic acid-based drug delivery system with pH-responsive dissociation for enhanced drug delivery

Improving the efficiency of drug delivery is one of the most important goals in the field of drug delivery. One strategy for drug delivery efficiency is to make the drug delivery system capable of charge reversal. In this study, we used hyaluronic acid (HA) as the skeleton to anchor dimethylmaleic anhydride-modified polylysine (PLL-DMMA) and N-(3-Aminopropyl)-imidazole (IMI) to construct a pH-sensitive (IMI/Zn2+)-HA-PLL-DMMA system via Zn coordination. The (IMI/Zn2+)-HA-PLL-DMMA system can detach DMMA moieties and expose PLL with a positive charge in the acidic tumor microenvironment (TME), which enhances cellular uptake in cancer cells through charge reversal. Once the drug-loaded (IMI/Zn2+)-HA-PLL-DMMA enters cancer cells, it specifically responds and disassembles in the acidic TME, resulting in drug release and inhibition of cancer cell viability. The (IMI/Zn2+)-HA-PLL-DMMA system is designed to regulate drug release behavior with Zn2+ and IMI groups as control units. The HA-based system shows synergistic selective drug delivery in suppressing tumor cells and has potential in cancer therapy.

PLXDC1 serves as a potential prognostic marker and involves in malignant progression and macrophage polarization in colon cancer.

The malignant behavior and immune escape ability of cancer cells lead to therapeutic failure and poor prognosis for patients with various cancers, including colon cancer. Plexin domain containing 1 (PLXDC1) was initially identified to exert key roles in tumor by regulating angiogenesis and has recently proved to be involved in cell proliferation and migration of glioblastoma and gastric cancer cells. However, its roles in colon cancer remain unclear. In this study, the online bioinformatics databases confirmed high expression of PLXDC1 in colon cancer specimens, which was associated with cancer stages and nodal metastasis. Similarly, the increased expression of PLXDC1 was also validated in our collected samples and colon cancer cells. Moreover, patients with high expression of PLXDC1 had shorter survival, indicating that PLXDC1 might be a potential prognostic predictor for colon cancer patients. Notably, targeting PLXDC1 inhibited cancer cell viability and invasion, and enhanced cell apoptosis. Intriguingly, Tumor Immune Estimation Resource database confirmed that PLXDC1 expression was related to various tumor-infiltrating immune cells in colon adenocarcinoma including macrophages, and its expression was also correlated with M2-like macrophage markers. In vitro, colon cancer cells with PLXDC1 downregulation had a reduced ability to recruit and polarize macrophage towards M2 phenotype by decreasing the percentage of CD206+ cells and M2-like markers (CD206, CD163, arginase1, and interleukin 10 [IL-10]). Moreover, PLXDC1 knockdown attenuated M2 macrophage-mediated promotion in cancer cell viability and invasion. Mechanically, inhibition of PLXDC1 suppressed activation of the IL-6/Signal transducer and activator of transcription 3 (STAT3) signaling. Reactivating the above pathway by transfection with IL-6 plasmids reversed the suppressive effects of PLXDC1 knockdown on cancer cell malignant behaviors, macrophage recruitment and M2-like polarization. Thus, PLXDC1 downregulation may inhibit the malignancy of colon cancer cells and their ability to recruit and polarize macrophages towards M2 phenotype by blocking the IL-6/STAT3 pathway. Together, targeting PLXDC1 may attenuate the progression of colon cancer by direct roles in cancer cells and indirect roles in macrophage polarization, representing a promising therapeutic target for colon cancer patients.

In Silico Study, Synthesis and Evaluation of Cytotoxic Activity of New Sulfonamide-Isatin Derivatives as Carbonic Anhydrase Enzyme Inhibitors

Aim: Design, molecular docking, synthesis, and evaluation of cytotoxic activity of new compounds I, II, III, and IV that have isatin-sulfonamide derivatives. Materials and Methods: for chemical synthesis, chemical compounds such as sulfonamide, 4-amino ethyl benzoate, isatin, and its derivatives were used. For the docking study (MOE), software program version 2015.10 was used. The MTT assay was utilized to predict the cytotoxic activity. Results: The synthesized compounds demonstrated significant inhibition of carbonic anhydrase XII activity through molecular docking, as well as significant inhibition of cancer cell viability. Compounds II and IV show higher S-scores than acetazolamide. Also, the MTT assay shows that compounds II and IV have IC50 values of 0.06 µM and 0.105 µM against MCF-7 cells, respectively, while acetazolamide has an IC50 value of 0.394 µM. While acetazolamide had an IC50 of 0.901 µM, compounds II and IV had IC50s of 0.063 µM and 0.114 µM against Hct116 cells, respectively. The MTT assay explains compounds II and IV have better cytotoxic activity compared with acetazolamide. Conclusion: New compounds that were produced showed signs of cytotoxicity and carbonic anhydrase inhibitory qualities.

The use of resveratrol in the fight against Cancer in women: a review

Cancer continues to be a major global health challenge, especially among women. Recent scientific studies have focused on resveratrol (RSV), a natural polyphenol found in various foods, as a potential supplementary therapy for cancer. This review assesses the existing evidence on resveratrol's effects on cancer cells, examining its mechanisms, potential benefits, and clinical implications. Research involved analyzing articles sourced from PUBMED with keywords: "(resveratrol) AND (cancer) AND (women)" (197 articles), "(resveratrol) AND (ovarian cancer)" (149 articles), and "(resveratrol) AND (endometrial cancer)" (21 articles). The selection was based on the specificity of results concerning resveratrol’s role in combating women’s cancer, with the most recent articles chosen in cases of redundancy. RSV has demonstrated capabilities to inhibit cancer cell viability and proliferation, including in breast cancer. It influences cell signaling, enhancing apoptosis and reducing tumor growth, and regulates cyclins and kinases to arrest the cell cycle, curbing uncontrolled cell division. RSV’s anti-inflammatory properties potentially suppress tumor progression, and its antioxidant activity activates enzymes to shield cells from oxidative harm, lowering cancer risks. Despite RSV’s promising potential, more research is needed to determine the ideal dosages, safety, and long-term impacts. Maintaining a diet rich in fruits, vegetables, and RSV-containing foods is vital for cancer prevention. RSV supplementation emerges as a promising support in combating cancer.

Discovery of a novel natural compound, vitekwangin B, with ANO1 protein reduction properties and anticancer potential.

Background: Prostate cancer and non-small cell lung cancer (NSCLC) present significant challenges in the development of effective therapeutic strategies. Hormone therapies for prostate cancer target androgen receptors and prostate-specific antigen markers. However, treatment options for prostatic small-cell neuroendocrine carcinoma are limited. NSCLC, on the other hand, is primarily treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors but exhibits resistance. This study explored a novel therapeutic approach by investigating the potential anticancer properties of vitekwangin B, a natural compound derived from Vitex trifolia. Methods: Vitekwangin B was chromatographically isolated from the fruits of V. trifolia. ANO1 protein levels in prostate cancer and NSCLC cells were verified and evaluated again after vitekwangin B treatment. Results: Vitekwangin B did not inhibit anoctamin1 (ANO1) channel function but significantly reduced ANO1 protein levels. These results demonstrate that vitekwangin B effectively inhibited cancer cell viability and induced apoptosis in prostate cancer and NSCLC cells. Moreover, it exhibited minimal toxicity to liver cells and did not affect hERG channel activity, making it a promising candidate for further development as an anticancer drug. Conclusion: Vitekwangin B may offer a new direction for cancer therapy by targeting ANO1 protein, potentially improving treatment outcomes in patients with prostate cancer and NSCLC. Further research is needed to explore its full potential and overcome existing drug resistance challenges.

EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling.

We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase-based TPDephos and the effective epidermal growth factor receptor (EGFR) tyrosine dephosphorylation. We also used phosphoproteomic approaches to study the signaling transductions affected by PhosTAC-related molecules at the proteome-wide level. This work demonstrated the differential signaling pathways inhibited by PhosTAC compared with the TKI, gefitinib. Moreover, a covalent PhosTAC selective for mutated EGFR was developed and showed its inhibitory potential for dysregulated EGFR. Last, EGFR PhosTACs, consistent with EGFR dephosphorylation profiles, induced apoptosis and inhibited cancer cell viability during prolonged PhosTAC treatment. PhosTACs showcased their potential of modulating RTKs activity, expanding the scope of bifunctional molecule utility.

Abstract 1224: 3D models of chemotherapy- and PARPi-resistant ovarian cancer indicate essential roles for JAK/STAT signaling in mediating drug resistance

Abstract Ovarian cancer is the deadliest gynecological cancer with a low 5-year overall survival rate that affects over 300,000 women globally each year. Given lack of routine screening procedures, ovarian cancer patients are frequently diagnosed with late-stage disease that rapidly progress despite initial responses to front line therapy. PARPi and VEGFi targeted therapies have improved progression free survival in small subsets of patients but have largely failed to improve overall survival. Since the robust uptake of PARPis in the front line setting, resistance to this class of drugs is a growing problem. The literature is filled with many novel treatment approaches, but the vast majority fail to gain traction in pre-clinical models and early phase trials. A contributing factor to these disappointments relates to the prevalent use of 2D monoculture model systems that do not recapitulate the tumor microenvironment. To address this issue, we utilized the Rastrum 3D cell printer to grow ovarian cancer cells and PDX models in bio-functional matrices which provide optimal stiffness and extracellular matrix components specific to the ovarian tumor microenvironment. We found that ovarian cancer cells grown under these conditions exhibit dramatic up-regulation of the JAK/STAT signaling pathway, including autocrine/paracrine signaling factors, which correlated with increased sensitivity to JAK/STAT inhibitors. This affect was lost when STAT1 and STAT3 knockout cell lines were grown in this 3D environment. Ovarian tumors are known to be rich in cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). We incorporated primary CAFs into this 3D culture system and found they could promote ovarian cancer cell growth only in cancer cells with intact JAK/STAT signaling further indicating the essential role of this pathway in mediating tumor progression. Co-culture with M2 macrophages was also found to induce ovarian cancer cell growth, particularly in resistant models. Conversely, co-culture with M1 macrophages inhibited treatment naïve ovarian cancer cell growth but not resistant cell line growth. Single-cell RNAseq of the complex 3D cultures elucidated profound differences in the cross-talk between these cell types that is dependent on cancer cell sensitivity to standard-of-care agents. Finally, the addition of JAK/STAT inhibitors was found to substantially alter this cross-talk between cell types and inhibit cancer cell viability. These data further implicate the importance of JAK/STAT signaling, specifically in clinically relevant 3D models, in supporting ovarian cancer progression and response to chemotherapy and PARPi treatment. Ongoing studies are aimed at confirming these findings in pre-clinical mouse models and to elucidate the most effective JAK/STAT inhibitors in vivo with the goal of informing the design of future clinical trials. Citation Format: Esther Rodman, Xiyin Wang, Hannah Smith, Xiaonan Hou, Scott Kaufmann, John Weroha, John Hawse. 3D models of chemotherapy- and PARPi-resistant ovarian cancer indicate essential roles for JAK/STAT signaling in mediating drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1224.

Impact of Quran Therapy as a Complementary and Alternative Medicine in Cancer

Cancer patients suffer from the deleterious effects of the disease and its treatment. Quran Recitation therapy has been used as Complementary and Alternative Medicine (CAM) by Muslims for multiple diseases including cancer. Objective: To find the impact of Quran recitation therapy as CAM in the management of cancer. Methods: The study included full-text original research articles from a 10-year pooled data (2013 to 2023). The studies were divided into three categories i.e., cancer cell cultures, animal models and cancer patients. Results: Quran recitation on cancer cell cultures revealed an inhibition of cancer cell viability, proliferation and migration. Animal studies revealed increased T lymphocyte activity among the cancer cells and human studies revealed a significant reduction of anxiety, stress, depression, pain, nausea and vomiting during cancer management. Thus, the addition of Quran recitation therapy as a complementary medicine along with the standard medical treatment improved the prognosis and reduced the side effects of cancer treatment. Conclusions: Based on this evidence, Quran recitation can be used as a safe, non‑pharmacological treatment to improve the management of cancer.

Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy

Metformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U–13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.

Biomimetic theranostic nanoparticles for effective anticancer therapy and MRI imaging

Cancer remains a leading cause of mortality worldwide, necessitating the development of innovative therapeutic approaches. Nanoparticle-based drug delivery systems have garnered significant interest due to their multifunctionality, offering the potential to enhance cancer treatment efficacy and improve patient tolerability. Membrane-coated drug delivery systems hold great potential for enhancing the therapeutic outcome of nanoparticle-based anticancer therapies. In this study, we report the synthesis of multifunctional iron-functionalized mesoporous polydopamine nanoparticles (MPDAFe NPs). These nanoformulations demonstrate substantial potential for combining efficient drug delivery and magnetic resonance imaging (MRI) and showcase the advantages of biomimetic coating with tumor cell-derived membranes. This coating confers prolonged circulation and improved the targeting capabilities of the nanoparticles. Furthermore, comprehensive biosafety evaluations reveal negligible toxicity to normal cells, while the combined chemo- and phototherapy exhibited significant cytotoxicity towards cancer cells. Additionally, the photothermal effect evaluation highlights the enhanced cytotoxicity achieved through laser irradiation, showcasing the synergistic effects of the nanomaterials and photothermal therapy. Importantly, our chemotherapeutic effect evaluation demonstrates the superior efficacy of doxorubicin-loaded MPDAFe@Mem NPs (cancer cell membrane-coated MPDAFe NPs) in inhibiting cancer cell viability and proliferation, surpassing the potency of free doxorubicin. This study comprehensively investigates theranostic, membrane-coated drug delivery systems, underlining their potential to increase the efficacy of cancer treatment strategies. The multifunctional nature of the iron-functionalized polydopamine nanoparticles allows for efficient drug delivery and imaging capabilities, while the biomimetic coating enhances their biocompatibility and targeting ability. These findings contribute valuable insights towards the development of advanced nanomedicine for improved cancer therapeutics.

Evaluation of anti-cancer effects of carnosine and melittin-loaded niosomes in MCF-7 and MDA-MB-231 breast cancer cells.

Background: We investigated the anti-cancer effect of carnosine-loaded niosomes (Car-NIO) and melittin-loaded niosomes (Mel-NIO) with olaparib in breast cancer cell lines (MCF-7 and MDA-MB-231). Methods: The thin film method was used for preparing the niosomes and characterized in terms of morphology, size, and polydispersity index (PDI). We further evaluated the impact of these peptides on breast cancer cells viability, RT-qPCR assays, malondialdehyde (MDA) activity, and cell cycle progression, to determine if these are linked to carnosine and melittin's anti-proliferative properties. Results: Car-NIO and Mel-NIO in vitro study inhibited cancer cell viability. They have also upregulated the expression of protein 53 (P53), BCL2-Associated X Protein (Bax), caspase-9, caspase-3, programmed cell death 4 (PDCD4), and Forkhead box O3 (FOXO3), while downregulated the expression of B-cell lymphoma 2 (Bcl2), poly (ADP-ribose) polymerase (PARP 1), and MicroRNA-183 (miRNA-183). The MCF-7 cells were arrested at the G2/M phase in Car-NIO, on the other hand, the MDA-MB-231 cells were arrested at the S phase. While the Mel-NIO and olaparib arrested the MCF-7 and MDA-MB-231 cells at the G0/1 phase. Conclusion: Our study successfully declared that Mel-NIO had more anti-cancer effects than Car-NIO in both MCF-7 and MDA-MB-231 breast cancer cells.

Long non‑coding RNA PTCSC3 suppresses triple‑negative breast cancer by downregulating long non‑coding RNA MIR100HG.

Long non-coding RNA (lncRNA) PTCSC3 is characterized as a tumor suppressor in thyroid cancer and glioma. The present study aimed to investigate the role of PTCSC3 in triple-negative breast cancer (TNBC). A total of 82 patients with TNBC were enrolled in the present study. The results showed that PTCSC3 was downregulated, while lncRNA MIR100HG was upregulated in tumor tissues compared with that in adjacent non-cancerous tissues of patients with TNBC. The follow-up study showed that low expression levels of PTCSC3 and high expression levels of MIR100HG were closely associated with poor survival of patients with TNBC. The expression levels of MIR100HG were decreased with the clinic stages of TNBC, while the expression levels of MIR100HG showed the opposite trend. Correlation analysis showed that the expression levels of PTCSC3 and MIR100HG were significantly correlated in both tumor tissues and adjacent non-cancerous tissues. The overexpression of PTCSC3 inhibited the expression level of MIR100HG in TNBC cells, while the expression level of PTCSC3 was unaffected. Cell Counting Kit-8 and Annexin V-FITC Apoptosis flow cytometry assays showed that overexpression of PTCSC3 led to inhibition, while overexpression of MIR100HG led to the promotion of TNBC cells viability and inhibited apoptosis of TNBC cells. In addition, overexpression of MIR100HG attenuated the effects of PTCSC3 overexpression on cancer cell viability. However, the overexpression of PTCSC3 did not affect cancer cell migration and invasion. Western-blot analysis showed that PTCSC3 suppressed viability and promoted apoptosis of TNBC cells through the Hippo signaling pathway. Thus, the present study demonstrated that lncRNA PTCSC3 inhibits cancer cell viability and promotes cancer cell apoptosis in TNBC by downregulating MIR100HG.

Inhibition of stemness and EMT by taxifolin ruthenium-p-cymene complex via downregulating the SOX2 and OCT4 expression on lung cancer

Lung carcinoma is perhaps the most often reported cancer incidence throughout the world. The flavonoid metal complexes have exhibited a potential chemotherapeutic effect. This study investigated the chemotherapeutic effect of taxifolin ruthenium-p-cymene complex against lung carcinoma through MTT assay, transwell migration assay, sphere formation assay, western blot, histopathology, immunohistochemistry, and TUNEL assay. The in silico study determined the target proteins of the complex. The synthesized organometallic complex was characterized via various spectroscopical techniques. The complex exhibited strong binding affinity for PI3K, EGFR, and β-catenin. The complex promoted apoptosis and inhibited the colony formation of the cancer cells. Moreover, the cancer cell migration and cancer stemness were reduced with decreased SOX2 and OCT4 expression. The complex induced cell cycle arrest at sub G0/G1 phase, S phase and G2/M phase and promoted caspase-3 mediated apoptosis. The in vivo study demonstrated successful restoration of lung tissue due to the treatment with the complex in benzo-α-pyrene induced lung cancer model. Additionally, the expression of p53 and caspase-3 was increased with significant downregulation of Akt, mTOR and β-catenin. In conclusion, the complex inhibited cancer cell viability, stemness, and EMT in both in vitro and in vivo model systems through the alteration of PI3K/Akt/mTOR/EGFR pathway and expression of stem cell markers including SOX2 and OCT4 that eventually abrogated the EMT mediated metastasis of cancer cells.

Statement of Retraction: New Co(II)-organic framework for cyanosilylation reactions and treatment effect against esophageal cancer by inhibiting cancer cell viability, migration, and invasion

This article refers to:New Co(II)-organic framework for cyanosilylation reactions and treatment effect against esophageal cancer by inhibiting cancer cell viability, migration, and invasion

Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins.

Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enable the transfer of ubiquitin tags onto their target proteins, leading to proteasomal degradation. However, several E3 ligases are validated pharmacological targets themselves, of which inhibitor of apoptosis (IAP) proteins are considered druggable in cancer. Here, we report three series of heterobifunctional PROTACs, which consist of an IAP antagonist linked to either von Hippel-Lindau- or cereblon-recruiting ligands. Hijacking E3 ligases against each other led to potent, rapid, and preferential depletion of cellular IAPs. In addition, these compounds caused complete X-chromosome-linked IAP knockdown, which was rarely observed for monovalent and homobivalent IAP antagonists. In cellular assays, hit degrader 9 outperformed antagonists and showed potent inhibition of cancer cell viability. The hetero-PROTACs disclosed herein are valuable tools to facilitate studies of the biological roles of IAPs and will stimulate further efforts toward E3-targeting therapies.

MicroRNA-129-3p Inhibits Colorectal Cancer Proliferation

MicroRNA-129-3p plays a pro-cancer role in colorectal cancer by down-regulating BIM. This study intends to assess its role in colorectal cancer cells. A total of 30 colorectal cancers and 10 paracancerous samples were obtained to measure MicroRNA-129-3p expression by PCR. Colorectal cancer cells were transfected with miR-129-3p mimic or inhibitor followed by analysis of cell growth, apoptosis. miR-129-3p expression was significantly lower in colorectal cancer tissues than that in cancer adjacent tissues (P <0.05). miR-129-3p overexpression after mimic transfection significantly inhibited cancer cell viability and promoted apoptosis (P < 0.05). Moreover, it also significantly downregulated E2F5, BIM and FoxO3a in colorectal cancer cells. Furthermore, E2F5 was targeted by miR-129-3p. In conclusion, miR-129-3p inhibits colorectal cancer cell proliferation via targeting E2F5 to downregulate BIM, indicating that it might be a target for treating colorectal cancer.

Trans-gnetin H isolated from the seeds of Paeonia species induces autophagy via inhibiting mTORC1 signalling through AMPK activation.

Paeonia is a well-known species of ornamental plants, traditional Chinese medicines, and emerging oilseed crops. Apart from nutritional unsaturated fatty acids, the seeds of peonies are rich in stilbenes characterized by their wide-ranging health-promoting properties. Although the typical stilbene resveratrol has been widely reported for its multiple bioactivities, it remains uncertain whether the trimer of resveratrol trans-gnetin H has properties that regulate cancer cell viability, let alone the underlying mechanism. Autophagy regulated by trans-gnetin H was detected by western blotting, immunofluorescence, and quantitative real-time PCR. The effects of trans-gnetin H on apoptosis and proliferation were examined by flow cytometry, colony formation and Cell Counting Kit-8 assays. Trans-gnetin H significantly inhibits cancer cell viability through autophagy by suppressing the phosphorylation of TFEB and promoting its nuclear transport. Mechanistically, trans-gnetin H inhibits the activation and lysosome translocation of mTORC1 by inhibiting the activation of AMPK, indicating that AMPK is a checkpoint for mTORC1 inactivation induced by trans-gnetin H. Moreover, the binding of TSC2 to Rheb was markedly increased in response to trans-gnetin H stimulation. Similarly, trans-gnetin H inhibited the interaction between Raptor and RagC in an AMPK-dependent manner. More importantly, trans-gnetin H-mediated autophagy highly depends on the AMPK-mTORC1 axis. We propose a regulatory mechanism by which trans-gnetin H inhibits the activation of the mTORC1 pathway to control cell autophagy.

P73α1, an Isoform of the p73 Tumor Suppressor, Modulates Lipid Metabolism and Cancer Cell Growth via Stearoyl-CoA Desaturase-1.

Altered lipid metabolism is a hallmark of cancer. p73, a p53 family member, regulates cellular processes and is expressed as multiple isoforms. However, the role of p73 in regulating lipid metabolism is not well-characterized. Previously, we found that loss of p73 exon 12 (E12) leads to an isoform switch from p73α to p73α1, the latter of which has strong tumor suppressive activity. In this study, comprehensive untargeted metabolomics was performed to determine whether p73α1 alters lipid metabolism in non-small cell lung carcinoma cells. RNA-seq and molecular biology approaches were combined to identify lipid metabolism genes altered upon loss of E12 and identify a direct target of p73α1. We found that loss of E12 leads to decreased levels of phosphatidylcholines, and this was due to decreased expression of genes involved in phosphatidylcholine synthesis. Additionally, we found that E12-knockout cells had increased levels of phosphatidylcholines containing saturated fatty acids (FAs) and decreased levels of phosphatidylcholines containing monounsaturated fatty acids (MUFAs). We then found that p73α1 inhibits cancer cell viability through direct transcriptional suppression of Stearoyl-CoA Desaturase-1 (SCD1), which converts saturated FAs to MUFAs. Finally, we showed that p73α1-mediated suppression of SCD1 leads to increased ratios of saturated FAs to MUFAs.

8-Hydroxyquinoline a natural chelating agent from Streptomyces spp. inhibits A549 lung cancer cell lines via BCL2/STAT3 regulating pathways.

Biomolecules from Streptomyces spp. are emerging sources of natural drugs and have been focused on over the decade. The discovery of bioactive chemotherapeutic molecules from soil Streptomyces spp. has opened the medium for the search for natural drugs. In the current study, 8-HOQ was extracted and purified from soil Streptomyces spp. and was evaluated on A549 and BEAS cell lines. The apoptotic and caspase mediated pathways were evaluated using cell proliferation, dual fluorescent staining, migration, invasion and mRNA as well as protein quantification of apoptotic markers. In vitro cytotoxicity test revealed that 8-HOQ possesses potent cytotoxicity activities with IC50values of 26µM, 5µM, 7.2µM at 24h, 48h, and 72h respectively against A549 lung cancer cell lines. The result also demonstrated that 8-HOQ from Streptomyces spp significantly inhibited the A549 lung cancer cell lines and activated the intrinsic pathways of apoptosis. The caspase-3 and caspase-8 activities were potentially elevated in 8-HOQ treated A549 cell lines and confirmed that 8-HOQ mediated A549 cancer cell death through the intrinsic pathway. The results explored caspase-mediated apoptosis as a mechanism underlying the inhibition of cancer cell viability in a dose-dependent manner. The expression of P53, BCL2 and STAT3 were inhibited in A549 cell lines and confirmed the metastasis inhibitory potential of 8-HOQ by blocking migration and invasion in A549 cell lines. These results indicated that 8-HOQ from Streptomyces spp. potentially inhibited growth and migration of A549 lung cancer cell lines.