Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients. OBJECTIVES: This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance. METHODS: We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor. CONCLUSIONS: This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies.

Opportunities and challenges for anti-CD47 antibodies in hematological malignancies.

CD47 is a cell-surface ligand that is overexpressed in various malignancies and that binds to SIRPα on macrophages to promote tumor cell evasion of phagocytosis. Blocking the CD47-SIRPα axis can increase the phagocytosis of macrophages to exert antitumor effects. CD47-based immunotherapy is a current research focus. The combination of anti-CD47 antibodies with other drugs has shown encouraging response rates in patients with hematological tumors, but side effects also occur. Bispecific antibodies and SIRPα/Fc fusion proteins appear to balance the efficacy and safety of treatment. We review the latest clinical research advances and discuss the opportunities and challenges associated with CD47-based immunotherapy for hematological malignancies.

Progress in molecular feature of smoldering mantle cell lymphoma.

Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as "smoldering MCL" (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.

[Effects of SmacN7 inducing apoptosis of breast cancer cell MDA-MB-157 and its mechanism].

Objective: To investigate the effects and molecular mechanisms of Second mitochondria-derived activator of caspase N7 (SmacN7) on the apoptosis of breast cancer cells MDA-MB-157. Methods: Breast cancer cells MDA-MB-157 were treated with SmacN7 at the concentrations of 0-20 µmol/L. The proliferation activity of the cells was detected by MTS method, apoptosis and cell cycle were analyzed by flow cytometry, karyotypic changes of MDA-MB-157 cells were observed by Hoechst33342 staining, mitochondrial membrane potential was detected by JC-1 staining, and LDH release experiment was used to detect the drug cytotoxicity. Real time PCR was used to analyze the transcription levels of genes in MDA-MB-157 cells. The effect of inhibiting breast cancer proliferation was confirmed by tumor inhibition experiments. Results: After treated with SmacN7, the inhibition rate of proliferation and apoptosis rate of breast cancer cells MDA-MB-157 were increased (P＜0.01), the karyotype changed significantly, the mitochondrial membrane potential in cells was decreased, and the LDH release was increased. The transcription levels of TRAIL, DR4, DR5, p53, PARP-1, Bax, Bid, BAK, caspase-3, caspase-8 and caspase-9 were up-regulated (P＜0.01), and the transcription levels of Ras, PI3K, AKT, mTOR, Bcl-2, Bcl-xL, MCL-1, Survivin, cIAP-1 and cIAP-2 were inhibited (P＜0.01). Conclusion: SmacN7 induces apoptosis of breast cancer cell MDA-MB-157 through TRAIL-mediated death receptor pathway and mitochondrial-mediated endogenous apoptosis pathway, and plays a role in anti-breast cancer.

[Effects of 2-12alkyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione(DMDD)on diffuse large B lymphoma and its mechanism].

OBJECTIVE: To investigate the effects and molecular mechanisms of 2-12alkyl-6-methoxycyclohexa-2,5-diene-1,4-dione(DMDD) on diffuse large B lymphoma (DLBCL). METHODS: In animal experiments, 4-week-aged BALB/C mice were divided into 5 groups, 20 mice in each group. Mice were inguinal injected with DLBCL cell line OCI-LY19 cells 0.1 ml at the concention of 1 × 107 /ml. Two days later, mice were treated with DMDD at the doses of 0, 1, 5, 25 and 125 mg/kg by intragastric administration respectively, once /2 days. Ten mice of each group were killed on the 18th day of administration, and the tumor tissues were weighed. The survival time of the remaining mice were recorded. In cell experiments, OCI-LY19 cells were added to 96-well culture plates, 100 µl 1×105 cells/ml per well, then 100 µl DMDD was added to the well and the final concentrations were 0, 1, 5, 25 and 125 µmol/L respectively. The cells were treated with DMDD for 0, 24, 48 and 72 h, three wells in each group. The cell proliferation activity was detected by MTS assay. According to the results of cell proliferation experiments, OCI-LY19 cells were treated with DMDD at the concentrations of 0 µmol/L, 5 µmol/L and 25 µmol/L for 24 h. The apoptosis rate was analyzed by flow cytometry, the nuclear type was observed by hoechst staining, the mitochondrial membrane potential was observed by JC-1 staining, cytotoxicity of drugs was evaluated by LDH release experiment, gene expression and transcription were analyzed by qPCR and Western blot. RESULTS: Compared with 0 mg/kg drug group, DMDD at the dose of 1～125 mg/kg could inhibit the growth of tumor tissue in mice and prolong their survival time (P＜0.01). Cell experiments showed: in DMDD group, the proliferation activity of OCI-LY19 cells was decreased significantly and the level of apoptosis was increased significantly (P＜0.01), nuclear fragmentation, agglutination, apoptotic bodies occurred and mitochondrial membrane potential was decreased, the LDH release rate was increased significantly (P＜0.01), the expressions of caspase-3 and bax genes and the phosphorylation level of Ikappa B alpha in cells were up-regulated significantly, the protein expression levels of bcl-2, bcl-xL, jak2 and stat3 were inhibited significantly (P＜0.01). CONCLUSION: DMDD can inhibit the expressions of JAK2, STAT3 and p-Ikappa B alpha in JAK2/STAT3 and NF-kappa B signal pathways, down-regulate BCL-2/BAX and activate Caspase-3, finally, activate the endogenous pathway of mitochondrial apoptosis in OCI-LY19 cells and promote the apoptosis of DLBCL cells, inhibit proliferation of OCI-LY19 cells. It has inhibitive effects on DLBCL.

[The effects of tectochrysin on prostate cancer cells apoptosis and its mechanism].

OBJECTIVE: To investigate the effects of tectochrysin on prostate cancer cell line 22Rv.1 and reveal its molecular mechanism. METHODS: Tectochrysin at the concentrations of 0～20 µg/ml was applied to 22Rv.1 cells and normal prostate cell RWPE-1. The proliferation activity of the cells was detected by MTS assay. Flow cytometry and hoechst 33342 staining were used to analyze the effects of drugs on cell apoptosis, death, cell cycle and nuclear type changes. LDH release test was used to analyze the cytotoxicity of the drug to 22Rv.1 cells. QPCR and Western blot were used to analyze the effects of the drug on the expressions of genes in 22Rv.1 cells. Finally, the tumor inhibited effect of the drug on the bearing tumor BALB/c mice were confirmed though anti-tumor experiment. RESULTS: Tectochrysin could significantly inhibit the proliferation activity of 22Rv.1 cells and induced their apoptosis, and promoted the expressions of genes dr4, dr5, trail, p53, caspase-3, caspase-8, caspase-9, bid, bax and foxo3, inhibited the expressions of anti-apoptotic genes akt, pi3k and bcl-2. CONCLUSION: Tectochrysin can induce prostate cancer cells apoptosis through affecting TRAIL and PI3K/AKT signaling pathways, and has anti-prostate cancer effect.

A meta-analysis of the efficacy of cognitive behavior therapy on quality of life and psychological health of breast cancer survivors and patients.

OBJECTIVE: The aim of this study was to examine the effect of cognitive behavior therapy (CBT) on quality of life (QOL) and psychological health of breast cancer survivors and patients. METHODS: A total of 1289 references were examined from an overall literature search in PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews. Randomized controlled trials assessing the efficacy of CBT compared with a range of comparators in cancer survivors. We assessed the effect of CBT by using the standardized mean difference as effect size. RESULTS: Among 1289 abstracts and 292 full-text articles reviewed, 10 studies were included. At the posttreatment period, the pooled effect size for CBT on QOL was 0.57 (95% CI, 0.44 to 0.69; P < .001), on depression was -1.11 (95% CI, -1.28 to -0.94; P < .001), on stress was -0.40 (95% CI, -0.53 to -0.26; P < .001), on anxiety was -1.10 (95% CI, -1.27 to -0.93; P < .001), and on hyperarousal cluster of symptoms was -0.18 (95% CI, -0.30 to -0.05; P < .001). The QOL was considered statistically medium effect sizes. The depression and anxiety were considered statistically large effect sizes. CONCLUSIONS: Cognitive behavior therapy is an effective therapy for psychological symptoms of cancer survivors and patients, with meaningfully clinical effect sizes. These findings suggested that CBT should be used as the intervention for breast cancer survivors and patients when possible.

[Anti-hepatoma effects of Smac analogue Birinapant and its related molecular mechanism].

OBJECTIVE: To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms. METHODS: Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 µg/kg) in each group after two days, once every other day.On 18th day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed. RESULTS: Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (P<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (P<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (P<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (P<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (P<0.01). CONCLUSIONS: Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.