Apoptotic Pathways In Cancer Cells Research Articles

Overcoming challenges in cancer treatment: Nano‐enabled photodynamic therapy as a viable solution

AbstractCancer presents a formidable challenge, necessitating innovative therapies that maximize effectiveness while minimizing harm to healthy tissues. Nanotechnology has emerged as a transformative force in cancer treatment, particularly through nano‐enabled photodynamic therapy (NE‐PDT), which leverages precise and targeted interventions. NE‐PDT capitalizes on photosensitizers activated by light to generate reactive oxygen species (ROS) that initiate apoptotic pathways in cancer cells. Nanoparticle enhancements optimize this process, improving drug delivery, selectivity, and ROS production within tumors. This review dissects NE‐PDT's mechanistic framework, showcasing its potential to harness apoptosis as a potent tool in cancer therapy. Furthermore, the review explores the synergy between NE‐PDT and complementary treatments like chemotherapy, immunotherapy, and targeted therapies, highlighting the potential to amplify apoptotic responses, enhance immune recognition of cancer cells, and inhibit resistance mechanisms. Preclinical and clinical advancements in NE‐PDT demonstrate its efficacy across various cancer types. Challenges in translating NE‐PDT into clinical practice are also addressed, emphasizing the need for optimizing nanoparticle design, refining dosimetry, and ensuring long‐term safety. Ultimately, NE‐PDT represents a promising approach in cancer therapy, utilizing the intricate mechanisms of apoptosis to address therapeutic hurdles. The review underscores the importance of understanding the interplay between nanoparticles, ROS generation, and apoptotic pathways, contributing to a deeper comprehension of cancer biology and novel therapeutic strategies. As interdisciplinary collaborations continue to thrive, NE‐PDT offers hope for effective and targeted cancer interventions, where apoptosis manipulation becomes central to conquering cancer.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Integrated Transcriptome and Molecular Docking to Identify the Hub Superimposed Attenuation Targets of Curcumin in Breast Cancer Cells.

Numerous in vitro and in vivo studies have shown that curcumin primarily activates apoptotic pathways in cancer cells and inhibits cancer progression by modulating various molecular targets. In this study, we utilized reverse docking servers to predict 444 human proteins that may potentially be targeted by curcumin. Then, high-throughput assays were conducted by using RNA-seq technology on curcumin-treated MCF-7 (human breast cancer ER (+)) and MDA-MB-231 (human breast cancer ER(-)/TNBC) cancer cell lines. Enrichment analysis identified seven and eight significantly down-regulated signaling pathways in these two cell lines, where the enriched genes were used to construct protein-protein interaction networks. From these networks, the MCODE algorithm screened out 42 hub targets, which are core genes of the RTK-(PI3K-AKT)/(MEK/ERK1/2) crosstalk network. Genetic alteration and expression patterns of hub targets of curcumin may be closely related to the overall pathogenesis and prognosis of breast cancer. MAPKAPK3, AKT3, CDK5, IGF1R, and MAPK11 are potential prognostic markers and therapeutic targets of curcumin in patients with triple-negative breast cancer. Molecular docking and transcriptomic results confirmed that curcumin can inhibit these high-scoring targets at the protein level. Additionally, these targets can act as self-feedback factors, relying on the cascading repressive effects in the network to limit their own transcription at the mRNA level. In conclusion, the integration of transcriptomic and molecular docking approaches enables the rapid identification of dual or multiple inhibitory targets of curcumin in breast cancer. Our study provides the potential elucidation of the anti-cancer mechanism of curcumin.

Cytotoxic action of the leaves of Uvaria chamae P.Beauv. and Dicliptera paniculata (Forssk.) I.Darbysh. from Nigeria mediated through intrinsic apoptotic pathway induction in four cancer cell lines

BackgroundOver the years, the morbidity and mortality due to cancer have continued to increase worldwide. Plants are well utilized in Nigeria ethno-medicine for cancer treatment. However, scientific evidence, particularly at the molecular level, has been lacking, and biodiversity loss is a threat. Aim of the studyThe cytotoxic activity of the leaves of six plants used in Nigeria ethno-medicine was investigated and the molecular pathway of cytotoxic action of two active extracts on four cancer cell lines (A549, RD, MCF-7, and HeLa) was also assessed. Materials and methodsCytotoxic activities of the plant extracts were assessed on breast (MCF-7), lung (A549), cervical (HeLa), adenocarcinoma and rhabdomyosarcoma (RD) cells using MTT cell viability assay in a time-dependent manner. The sandwich ELISA method was used to assess the protein expressions (Bcl-2, BAX, and executioner caspase 3) involved in the apoptotic pathway in cancer cells after treatment with cytotoxic extracts. UHPLC-MS/MS approach was used to analyze the possible bioactive phytochemicals of the cytotoxic plant extract. ResultsUvaria chamae and Dicliptera paniculata extracts displayed good cytotoxicity across all cell lines in a time- and concentration-dependent manner (CC50 <30 µg/mL). Increased pro-apoptotic BAX and lowered expression of anti-apoptotic Bcl-2 show the cytotoxic action of the two extracts followed the intrinsic apoptotic pathway compared to untreated cells. The increased expression of executioner caspase 3 indicated that the intrinsic apoptotic pathway was caspase-dependent. ConclusionThe anticancer potential of U. chamae and D. paniculata in this study validates the use of these plants in Nigerian ethno-medicine, highlighting apoptosis as a molecular pathway of their cytotoxicity.

IL-13 and the hydroperoxy fatty acid 13(S)HpODE play crucial role in inducing an apoptotic pathway in cancer cells involving MAO-A/ROS/p53/p21 signaling axis.

This study depicted the effect of IL-13 and 13(S)HpODE (the endogenous product during IL-13 activation) in the process of cancer cell apoptosis. We examined the role of both IL-13 and 13(S)HpODE in mediating apoptotic pathway in three different in vitro cellular models namely A549 lung cancer, HCT116 colorectal cancer and CCF52 GBM cells. Our data showed that IL-13 promotes apoptosis of A549 lung carcinoma cells through the involvement of 15-LO, PPARγ and MAO-A. Our observations demonstrated that IL-13/13(S)HpODE stimulate MAO-A-mediated intracellular ROS production and p53 as well as p21 induction which play a crucial role in IL-13-stimulated A549cell apoptosis. We further showed that 13(S)HpODE promotes apoptosis of HCT116 and CCF52cells through the up-regulation of p53 and p21 expression. Our data delineated that IL-13 stimulates p53 and p21 induction which is mediated through 15-LO and MAO-A in A549cells. In addition, we observed that PPARγ plays a vital role in apoptosis as well as in p53 and p21 expression in A549cells in the presence of IL-13. We validated our observations in case of an in vivo colon cancer tumorigenic study using syngeneic mice model and demonstrated that 13(S)HpODE significantly reduces solid tumor growth through the activation of apoptosis. These data thus confirmed that IL-13>15-LO>13(S)HpODE>PPARγ>MAO-A>ROS>p53>p21 axis has a major contribution in regulating cancer cell apoptosis and further identified 13(S)HpODE as a potential chemo-preventive agent which can improve the efficacy of cancer treatment as a combination compound.

Theoretical Study on the Binding Properties of Inhibitors to Myeloid Cell Leukemia 1

Myeloid leukemia 1 (Mcl-1) is a key anti-apoptotic member of the Bcl-2 protein family, and its overexpression or upregulation has been found in numerous cancer cells, which not only leads to tumorigenesis mediated by apoptotic escape modality, but also causes resistance to multiple subsequent anti-cancer therapies. The development of small molecule inhibitors that specifically target Mcl-1 and restore the blocked apoptotic pathway in cancer cells has emerged as a realistic solution for oncology drug design. Therefore, an in-depth study of the mechanism of action of inhibitors with Mcl-1 is important for the design of efficient drugs targeting Mcl-1. In this study, using molecular dynamics (MD) simulations, correlation analysis and principal component analysis, we revealed that the binding of inhibitors significantly altered the kinetic behavior of Mcl-1 and led to a conformational rearrangement of Mcl-1. Subsequently, the molecular mechanics-generalized Born surface area (MM-GBSA) method was used to further explore the binding ability of different inhibitors to Mcl-1, and the results showed that the calculated binding free energies agreed well with the experimental values, and van der Waals interactions and electrostatic interactions provided the main favorable contribution in the binding of inhibitors to Mcl-1. Furthermore, the interaction analysis showed a large number of hydrophobic interactions and hydrogen bonding between the inhibitor and Mcl-1. Finally, the residues F228, M231, M250, V253, T266, L267 and F270 and R263 were identified by residue-based free energy decomposition calculations to provide important energetic contributions to the binding of the inhibitor to Mcl-1 and could be key targets for the design of Mcl-1 inhibitors.

Mitochondrial dynamics and oxidative phosphorylation as critical targets in cancer.

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional, and the full range of mechanistic inter-connections are still being unravelled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model, although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

Green synthesized silver nanoparticles with mushroom extracts of Paxina leucomelas and Rhizopogon luteolus induce ROS-Induced intrinsic apoptotic pathway in cancer cells

The green synthesized silver nanoparticles (AgNPs) provide many advantages including the production of nanoparticles without using toxic compounds and solvents, the low-cost of the synthesis process, the existence of a large number of biological substances as a reducing agent of silver, and the production of nanoparticles in desired parameters. In this study, the PL-AgNPs and RL-AgNPs were synthesized by microwave-assisted green synthesis method using extracts of Paxina leucomelas and Rhizopon luteolus. The synthesized P. leucomelas-AgNPs (PL-AgNPs) and R. luteolus-AgNPs (RL-AgNPs) were characterized by UV–Vis, FTIR, XRD, DLS, S-TEM, and EDS analysis. Anticancer activity of the synthesized AgNPs was investigated on human cancer cells lines. Obtained results demonstrated that the PL-AgNPs and RL-AgNPs decreased cancer cell viability via ROS-mediated intrinsic apoptotic pathways. These findings strongly suggest that the AgNPs formed by aqueous extracts of P. leucomelas and R. luteolus may be introduced as an alternative apoptosis inducer in cancer drug discovery.

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

5‐Aza‐2’‐deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’‐deoxycytidine (dC) to 5‐methyl‐dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM‐13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti‐proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off‐target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.

Curcumin: An Insight into Molecular Pathways Involved in Anticancer Activity.

Curcuma longa has been mentioned in the Indian system of medicine for the management of a wide range of diseases. C. longa and its metabolites like curcumin, ar-turmerone, methylcurcumin, demethoxy-curcumin, and bisdemethoxycurcumin have also been reported to be beneficial in various types of cancer. Curcumin elicits anticancer properties chiefly by triggering apoptotic pathways in cancer cells. The properties are facilitated through diverse signaling pathways viz. pathways mediated by NF-kB, WNT/β-catenin pathway COX-2, LOX, STAT3, prostaglandin E2, phosphorylase kinase, VEGF, AKT, AP1, STAT3, PI3K, Akt, mTOR, ERK5, AP-1, TGF-b, PPARc, EBPa, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4, etc. The present article highlights curcumin biosynthesis, phytochemistry and diverse molecular pathways involved in regulating several types of secondary messengers to exhibit anticancer activity in almost all the forms of cancer.

Enhanced porphyrin-based fluorescence imaging-guided photodynamic/photothermal synergistic cancer therapy by mitochondrial targeting

Mitochondria are the power plants of the cell and play key roles in activating the apoptotic pathway in cancer cells, which are readily susceptible to cytotoxic reactive oxygen species and temperature elevations. Herein, we develop a “nanomissile” that targets mitochondria to enhance tumor treatment effects by facilitating mitochondrial dysfunction and releasing cytochrome C to activate the apoptotic pathway of cancer cells under 650-nm laser irradiation. Porphyrin-grafted polydopamine nanomaterial (PTPF-MitP) is designed as a nanomissile, with integrated O2-evolving photodynamic therapy and moderate photothermal therapy, which can selectively deliver to the mitochondria through a targeting unit, MitP. The cytotoxicity of PTPF-MitP to human lung tumor cells is twice as high as that of PTPF that does not have mitochondrial targeting units. In addition, it represents a realtime visualization and highly efficient treatment for tumor sites in vivo. This development represents a viable strategy for cancer therapy.

Abstract 1929: Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro

Abstract Previously we have shown that progesterone and calcitriol induce apoptosis of cancer cells. However, the apoptotic mechanisms of the two agents have not been well characterized yet. Herein, we investigated the molecular mechanisms of how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24h. Caspase 9 activity was increased in all cell lines after 24h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells. Citation Format: Latoya Mcglorthan, Ana Paucarmayta, Yovanni Casablanca, George L. Maxwell, Viqar Syed. Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro [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 1929.

Dose-dependent Effects of Vitamin C on Cancer Regulation: A Review

Vitamin C is a part of cell physiology and is utilized in many metabolic reactions. Therapeutically, it was found useful in many ailments including fatal diseases such as cancer. It has ability to induce apoptotic pathway in cancer cells in order to kill them within the body at lower concentrations without affecting the non-cancerous cells.

Apoptotic Cell Death Induction Through Pectin, Guar Gum and Zinc Oxide Nanocomposite in A549 Lung Adenocarcinomas

Previously, we reported the immunostimulatory potential of the nanocomposite prepared from biopolymers (Pectin and Guar gum) and zinc oxide (Pec-gg-ZnO) on human peripheral-blood lymphocytes leading to enhanced anti-cancer immunity. The current study aims to describe the direct anti-cancer potential of Pec-gg-ZnO nanocomposite and the relevant mechanism of cell death induction in human lung carcinomas (A549). The cytotoxicity assay revealed the anti-cancer potential of Pec-gg-ZnO nanocomposite towards A549 cells, cervical adenocarcinoma (HeLa), and prostatic small cell carcinoma (PC-3). The IC50 values were 83.67 ± 0.10 μg/ml, 87.25 ± 0.03 μg/ml and 85.95 ± 0.03 μg/ml for A549, HeLa and PC-3 cells, respectively. The nanocomposite's cancer cells' killing capabilities were significantly higher than pectin and guar gum alone. Hemolysis assay revealed that synthesized Pec-gg-ZnO nanocomposite is biocompatible at 2.5 mg/ml. S phase arrest with enhanced sub-G1 (apoptotic cells) population was examined in A549 cells treated with Pec-gg-ZnO nanocomposite. The nanocomposite caused apoptosis of target cells by inducing mitochondrial depolarisation, reactive oxygen species generation, caspase-3 and Poly (ADP-ribose) polymerase 1 (PARP1) activation resulting in DNA fragmentation. Collectively, the current data revealed that Pec-gg-ZnO nanocomposite is a novel polymer-based anti-cancer agent capable of inducing apoptotic pathways in cancer cells.

Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro

Previously we have shown inhibition of endometrial cancer cell growth with progesterone and calcitriol. However, the mechanisms by which the two agents attenuate proliferation have not been well characterized yet. Herein, we investigated how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24h. Caspase 9 activity was increased in all cell lines after 24h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells.

Correction to: Bioformulated Hesperidin-Loaded PLGA Nanoparticles Counteract the Mitochondrial-Mediated Intrinsic Apoptotic Pathway in Cancer Cells

Correction to: Bioformulated Hesperidin-Loaded PLGA Nanoparticles Counteract the Mitochondrial-Mediated Intrinsic Apoptotic Pathway in Cancer Cells

Abstract 596: Endolysosomal trafficking defects leads to caspase independed cell death in colon cancer

Abstract Currently approved conventional chemotherapeutics for treating colorectal cancer (CRC) exert their effect through activating apoptotic pathways in cancer cells. However, CRC cells often become resistant due to mutations in apoptotic pathways rendering chemotherapeutics ineffective. Drug resistant CRC typically advances to metastatic stage, resulting in poor prognosis and shorter survival time. We have recently discovered structurally constrained 4-pyridynyl BAPT compounds that cause a form of non-apoptotic cell death in CRC cells characterized by the simultaneous induction of dysregulated macropinocytosis (i.e. self-drinking) and macroautophagy (i.e. self-eating). We define this distinctive type of caspase-independent cell death as ‘methuophagy' (from the Greek ‘methuo', to drink to intoxication, and ‘phagy', self-eating). In particular, our initial lead, BAPT-27, does not induce cell death via activation of the classical apoptotic pathways, but causes methuophagy in submicromolar range. BAPT-27 induces substantial accumulation of fluid-filled, heterogeneous vacuoles and autophagosomes, resulting in metabolic failure, loss of membrane integrity, and detachment of cells from the substratum. The cell death is accompanied by extensive autophagy in the absence of cell shrinkage, chromatin condensation, alterations in mitochondrial membrane potential, or damage to the nuclear membrane. Other hit analogues i.e. BAPT-36, BAPT-38, BAPT-54 also potently trigger this form of non-apoptotic cell death in CRC cells. We observed that methuophagic cell death is accompanied by a significant increase in lysosomal activity, numbers, and biogenesis as confirmed by ultrastructural imaging. Our results suggest that BAPT analogues produce endolysosomal trafficking defects that prevent recycling of lysosomes and cause lysosome-to-nucleus signaling defect, a mechanism that disturb cellular clearance and energy metabolism. Furthermore, they disrupt vesicular trafficking at the lysosomal nexus, manifested by defective processing of procathepsins, impairment of autophagic flux, V-ATPase levels, and accumulation of autophagosomes and acrgo protein p-62. However, specific changes in core pharmacophore could result in loss of methuophagy induction and drive the cell death towards apoptosis. For example, BAPT-42 was found to have limited effects on lysosomal pathways and does not kill the cells through methuophagy, but induces apoptosis. Identifying the biology of methuophagy-induced cell death and lysosomal clearance pathways will allow us to better design this new class of compounds that kill CRC cells via non-apoptotic mechanisms for treatment of patients with apoptotic-resistant and aggressive CRCs. Citation Format: Noor Hussein, Mariah Pasternak, Shikha Kumari, Zaynah Awthe, William Gunning, Paul C. Trippier, Amit Tiwari. Endolysosomal trafficking defects leads to caspase independed cell death in colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 596.

To Study theAnti-cancer Effects of Shigella Flexneri in AspC-1 Pancreatic Cancer Cell Line in Approach to Bax and bcl-2 Genes.

Cancer is the uncontrolled division of cells and can be caused by genetic or environmental factors. Pancreatic cancer is one of the deadliest among all cancers. The role of bacteria as an anticancer agent dates back to almost 100years ago. The microbiome has recently become a focus of research in carcinogenesis and even pancreatic cancer. Shigella flexneri is a gram-negative bacterium, which causes shigellosis with symptoms such as diarrhea, fever, and stomach cramps in human. Shigella flexneri may play a very important role in the internal pathways of apoptosis and may induce apoptosis in some of the cancerous cells. In this experiment bacteria were cultured on Salmonella-Shigella agar, then inoculated into BHI Broth medium. After sonication, the protein concentration of the bacterium was measured by using the ZellBio Sensitive Protein Bradford Assay kit. MTT assay was performed to obtain IC50 for the said bacterial protein. Later by cDNA kit synthesized the cDNA based on the RNA template. In the end, the results were analyzed using real-time PCR and the expression of Bax and Bcl-2 genes was measured before and after treatment. The results showed that Shigella flexneri has the potential anti-proliferative effect in pancreatic cancer. The inhibitory concentration, pro-apoptotic amount to upregulate Bax, and meanwhile also to downregulate the bcl-2 found to be 10μl. In general, due to defects in the apoptotic pathway in cancer cells and the existence of drug-resistant cells, the detection of new apoptotic inducers such as Shigella flexneri cell extract can be used for further studies on cancer therapy.

Selective cytotoxic activity and protective effects of sodium ascorbate against hepatocellular carcinoma through its effect on oxidative stress and apoptosis in vivo and in vitro

ABSTRACT Objectives: Hepatocellular carcinoma (HCC) is characterized by elevated in oxidative stress and inflammatory cytokines, which enhance destructive effects of the tumor. Therefore, we conducted this study to investigate the protective effects of sodium ascorbate against thioacetamide-induced HCC in rats through studying its effect on the apoptotic pathway in rats. In addition, in vitro activity of sodium ascorbate was investigated on HepG2 and compared with cisplatin. Methods: HCC was experimentally induced by injecting rats with 200 mg/kg thioacetamide intraperitoneally twice weekly for 16 weeks. Part of HCC rats was concomitantly treated with 100 mg/kg sodium ascorbate intraperitoneally during the 16-week period. Hepatic tissues were used for the determination of NFκB, Nrf2, TNF-α, caspase-3, caspase-8 and caspase-9. Results: Sodium ascorbate significantly attenuated HCC-induced reduction in the expression of NrF2 associated with a reduction in concentrations of hydrogen peroxide and superoxide anion. In addition, sodium ascorbate blocked HCC-induced increase in the expression of NFκB and TNF-α. Sodium ascorbate slightly increased the activity of caspase-3, -8 and -9 in vitro but inhibited their activities in vivo. Conclusion: In spite of the antioxidant and anti-inflammatory activity of sodium ascorbate, it produced selective cytotoxic activity via direct activation of the apoptotic pathway in cancer cells without affecting the apoptotic pathway in normal hepatic cells.

Synthesis of cucurbitacin IIa derivatives with apoptosis-inducing capabilities in human cancer cells.

Twenty-one cucurbitacin IIa derivatives were synthesized and screened for cytotoxic activity. Their structures were established using 1H NMR, 13C NMR, and LC-MS spectroscopic data. The absolute configuration of the derivatives was determined by single crystal diffraction. In sulforhodamine B (SRB) assays, nearly all compounds displayed low cytotoxicity toward normal human cells (HEK293). However, some derivatives displayed high cytotoxicity, in the low μM range, toward several human tumor cell lines (SKOV3, HT29, HEPG2, MCF-7, and LOVO). Low IC50 values were obtained, especially for acetyl-protected product 2, 2,4,6-trichlorophenylhydrazine derivative 4a, and 2-hydrazinopyridine derivative 4d. In particular, compounds 2 and 4d showed low IC50 values of 1.2 ± 0.01 and 2.2 ± 0.19 μM against SKOV3 cells. These compounds were submitted to extensive biological testing, which showed that compounds 2 and 4a did not inhibit tumor cells by influencing the cell cycle. Furthermore, compound 4a triggered the apoptotic pathway in cancer cells, showing high apoptosis ratios. This study mainly changed the structure of cucurbitacin tetracyclic triterpenoids and provided a novel tetracyclic skeleton derived from natural products that provided further references for the future modification of cucurbitacin tetracyclic triterpenoids.

First-in-Human Study of Abbv-621, a TRAIL Receptor Agonist Fusion Protein, in Patients (Pts) with Relapsed/Refractory (RR) Acute Myeloid Leukemia (AML) and Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Apoptotic cell death can be triggered by activation of extrinsic and intrinsic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, binds to its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) to selectively activate the extrinsic apoptotic pathway in cancer cells. ABBV-621 is a second-generation TRAIL receptor agonist with antitumor activity as monotherapy (621-mono) in preclinical models of AML and DLBCL. The intrinsic apoptotic pathway is regulated by the BCL2 protein family, commonly overexpressed in hematologic malignancies. Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. In preclinical and xenograft models of AML and DLBCL, the ABBV-621 and VEN combination (621-VEN) had antitumor activity superior to either agent alone. This first-in-human study evaluated ABBV-621 as single agent and in combination in pts with advanced solid tumors and hematologic malignancies (NCT03082209). Safety and tolerability of ABBV-621 in advanced solid tumors have previously been presented (Ratain et al. J Clin Oncol 2019;37[suppl]: abstr 3013). Here, we report preliminary data for 621-mono in pts with RR AML and for 621-VEN in pts with RR AML and DLBCL. Methods: Adult pts with RR AML or DLBCL (ECOG 0-2) were enrolled. Pts with AML received ABBV-621 at 1.25-, 3.75-, 7.5-mg/kg doses in the 621-mono and at 3.75-mg/kg dose in the 621-VEN arms. Pts in the DLBCL 621-VEN arm received ABBV-621 at 3.75- and 7.5-mg/kg doses. ABBV-621 was administered intravenously on D1, 8, and 15 of a 21-D cycle; in 621-VEN cohorts pts received 400 mg oral VEN daily, and could be escalated to 800 mg. The primary endpoint was safety. In addition, preliminary antitumor efficacy and ABBV-621 binding to decoy receptors on neutrophils from peripheral blood were assessed. Results: As of Jun 2019, 17 pts were enrolled. Pts in AML 621-mono arm (1.25 [1], 3.75 [1], 7.5 [2] mg/kg): 1 male; median (med) age, 75 yr (range 71-82); med prior treatments, 2.5 (range 1-4); med time on treatment, 15 D (range 1-70). Pts in AML 621-VEN arm (3.75 mg/kg [7]): 5 male; med age, 71 yr (60-79); med prior treatments, 2 (1-2); med time on treatment, 26 D (1-77). Pts in DLBCL 621-VEN arm (3.75 [3], 7.5 [3] mg/kg): 4 male; med age, 57 yr (40-75); stage 4 (3); med prior treatments, 2.5 (1 to ≥5); med time on treatment, 26 D (8-36). One pt in the AML 621-VEN 3.75-mg/kg dose cohort had increases in alanine aminotransferase, aspartate aminotransferase and bilirubin as dose-limiting toxicities. Sixteen pts experienced adverse events (AEs) irrespective of causality. A summary of AEs is shown in Table. One pt in the AML 621-mono 7.5-mg/kg dose cohort died due to AML progression, unrelated to ABBV-621. Antitumor activity was observed in 1 pt in the AML 621-VEN arm (with complex cytogenetics and TP53 mutation) who reached complete remission (CR). One pt in the DLBCL 621-VEN 3.75-mg/kg cohort had stable disease, 2 with AML had resistant disease (1 in 621-mono [7.5 mg/kg] and 1 in 621-VEN), and 7 had progressive disease (PD; 1 in AML 621-mono [1.25 mg/kg], 2 in AML 621-VEN, and 4 in DLBCL 621-VEN [2 each in 3.75- and 7.5-mg/kg] cohorts). Using flow cytometry, saturation of ABBV-621 binding to decoy receptors on neutrophils was observed at 2 h postdosing, followed by dose-dependent desaturation of receptors in pts with DLBCL at 48-168 h. In AML 621-VEN pts, ABBV-621 remained bound to decoy receptors for up to 168 h; in DLBCL 621-VEN pts, the duration of binding was higher at ABBV-621 7.5 mg/kg compared with 3.75 mg/kg. In AML, the baseline frequency of myeloblasts was higher in pts with PD than CR, while that of myelomonocytes was higher in the pt with CR. The frequency of myeloblasts and myelomonocytes expressing DR4 and DR5 at baseline was highest in the pt with CR (Figure). Conclusions: ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML. Disclosures de Jonge: Faron Pharmaceuticals Ltd.: Consultancy. Carneiro:Actuate Therapeutics: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Medimmune: Research Funding; Astellas: Research Funding; AbbVie: Research Funding. Devriese:MSD: Consultancy. Penugonda:AbbVie: Employment, Other: Stock/stock options. Petrich:Abbvie: Employment, Equity Ownership. Nuthalapati:AbbVie: Employment, Other: Stock/stock options. Motwani:AbbVie: Employment, Other: Stock/stock options. Modi:AbbVie: Employment, Other: Stock/stock options. Chang:AbbVie: Employment, Other: Stock/stock options. Calvo:Celgene: Consultancy; Roche/Genentech: Consultancy, Other: travel/accommodations/expenses; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; PsiOxus: Consultancy; Amcure: Consultancy; START: Other: stock/ownership interests, Research Funding; Janssen-Cilag: Consultancy; EUSA Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Oncoart Associated: Other: stock/ownership interests; Guidepoint Global: Consultancy; Nanobiotix: Consultancy; HM Hospitales Group: Honoraria; AbbVie: Consultancy; BeiGene: Research Funding; Servier: Consultancy; International Cancer Consultants: Other: stock/ownership interests; Foundation INTHEOS: Other: president and founder; Gerson Lehrman Group: Consultancy; Pfizer: Consultancy. Moreno:Puma Biotechnology: Consultancy; Sanofi/Regeneron: Other: travel/accommodations/expenses.