Anticancer mechanisms of ß-carbolines.

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses.

AIM: Through network pharmacology, molecular docking, molecular dynamics in combination with experimentation, we explored the mechanism whereby 1-ethoxycarbonyl-beta-carboline (EBC) regulates the M2 polarization of tumor-associated macrophages. METHODS: Network pharmacology was adopted for analyzing the targets and signaling pathways related to the M2 polarization of EBC-macrophages, small molecular-protein docking was employed to analyze the possibility of EBC bonding to related protein, and molecular dynamics was introduced to analyze the binding energy between EBC and HDAC2. The M2 polarization of RAW264.7 macrophages was triggered in vitro by IL-4. After EBC intervention, the expressions of M1/M2 polarization-related cytokines were detected, and the mechanism of EBC action was explored in HDAC2-knockout RAW264.7 macrophages. A tumor-bearing mouse model was established in vitro to find the impact of EBC on tumor-associated M2 macrophages. RESULTS: As revealed by the network pharmacology, molecular docking and molecular dynamics analyses, EBC was associated with 51 proteins, including HDAC2, NF-κB and HDAC4. Molecular docking and dynamics analyses suggested that HDAC2 was the main target of EBC. In vitro experiments discovered that EBC could hinder the M2 polarization of RAW264.7 macrophages, which exerted insignificant effect on the M1-associated cytokines, but could lower the levels of M2-associated cytokines. After knocking out HDAC2, EBC could not further inhibit the M2 polarization of macrophages. At the mouse level, EBC could hinder the tumor growth and the tissue levels of M2 macrophages, whose effect was associated with HDAC2. CONCLUSION: Our study combining multiple methods finds that EBC inhibits the HDAC2-mediated M2 polarization of macrophages, thereby playing an anti-tumor role.

Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women.

INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.

3-Amide-ß-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents.

ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.

ß-Carboline (FG-7142) modulates fear but not anxiety-like behaviour in zebrafish.

The ß-Carboline FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site on the GABA-A receptor that induces anxiogenic, proconvulsant, and appetite-reducing effects in many species, including humans. Seizure-kindling effects have been well studied, however anxiogenic properties are relatively unexplored. This study aimed to investigate concentration-dependent effects of FG-7142 on anxiety-like behaviour and fear responses in zebrafish (Danio rerio) using the open-field test (OF) and novel object approach test (NOA). A U-shaped distribution was found with maximal responses in increased immobility and reduced distance moved at 10 µM in the NOA but not the OF. Follow up experiments demonstrated a lack of effect in repeated OF testing and no changes in opercular movements. Furthermore, the effect of FG-7142 was reversed with ethanol treatment. These results suggest that FG-7142 elicits a 'freezing' response in zebrafish via the introduction of novelty, suggesting fear-induction. These findings indicate that FG-7142 may act as an agent to promote acute fear responses in zebrafish.

Anticancer Potential of ß-Carboline Alkaloids: An Updated Mechanistic Overview.

his comprehensive review is designed to evaluate the anticancer properties of ß-carbolines derived from medicinal plants, with the ultimate goal of assessing their suitability and potential in cancer treatment, management, and prevention. An exhaustive literature survey was conducted on a wide array of ß-carbolines including, but not limited to, harmaline, harmine, harmicine, harman, harmol, harmalol, pinoline, tetrahydroharmine, tryptoline, cordysinin C, cordysinin D, norharmane, and perlolyrine. Various analytical techniques were employed to identify and screen these compounds, followed by a detailed analysis of their anticancer mechanisms. Natural ß-carbolines such as harmaline and harmine have shown promising inhibitory effects on the growth of cancer cells, as evidenced by multiple in vitro and in vivo studies. Synthetically derived ß-carbolines also displayed noteworthy anticancer, neuroprotective, and cognitive-enhancing effects. The current body of research emphasizes the potential of ß-carbolines as a unique source of bioactive compounds for cancer treatment. The diverse range of ß-carbolines derived from medicinal plants can offer valuable insights into the development of new therapeutic strategies for cancer management and prevention.

Identification of a ß-Carboline Alkaloid from Chemoselectively Derived Vanilla Bean Extract and Its Prevention of Lipid Droplet Accumulation in Human Hepatocytes (HepG2).

Targeting bioactive compounds to prevent lipid droplet accumulation in the liver, we explored an antioxidative extract from vanilla bean (Vainilla planifolia) after chemo-selective derivatization through heating and acid modification. The chemical analysis of vanilla bean extract through chemoselective derivatization resulted in the identification of sixteen compounds (34-50) using LC-MS/MS analysis. A ß-carboline alkaloid with a piperidine C-ring and a vanillin moiety at C-1 (34) was identified by molecular networking and diagnostic fragmentation filtering approaches. ß-carboline alkaloid 34 exhibited significant inhibitory activity of lipid droplet accumulation (LDAI) in oleic acid-loaded hepatocellular carcinoma HepG2 cells. The LDAI activity was associated with both activation of lipolysis and suppression of lipogenesis in the cells. The study indicates that crude plant extracts, following chemoselective derivatization, may contain bioactive compounds that could be beneficial in preventing hepatosteatosis and could serve as a source of lead compounds for drug development. This approach may be useful to investigate other mixtures of natural products and food resources.

Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin's highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.

[Dumai moxibustion combined with low-dose tadalafil for erectile dysfunction: Evaluation of therapeutic effect].

OBJECTIVE: To investigate the clinical effect of dumai (governor meridian) moxibustion combined with low-dose tadalafil in the treatment of ED with decline of vital gate fire. METHODS: We enrolled in this study 130 ED patients with decline of vital gate fire who met the inclusion criteria and equally randomized them into a control and an experimental group, the former treated with low-dose tadalafil tablets at 5 mg once a day while the latter by dumai moxibustion once a week in addition, all for 4 weeks. Of the total number of subjects, 62 in the control group and 63 in the experimental group completed the experiment. We recorded the scores on IIEF-5, Erection Quality Scale (EQS), Erection Hardness Scale (EHS), TCM symptoms and Treatment Satisfaction Scale (TSS) as well as the penile hemodynamic parameters peak systolic velocity (PSV), end diastolic velocity (EDV) and resistance index (RI) before and after treatment and compared them between the two groups. RESULTS: The total response rate was significantly higher in the experimental group than in the control (87.30% vs 66.13%, P < 0.05). IIEF-5, EQS, EHS and TSS scores, PSV and RI were markedly increased while TCM symptoms and EDV remarkably decreased in both groups after treatment (P < 0.05), even more significantly in the experimental than in the control group (P < 0.05). CONCLUSION: Dumai moxibustion combined with low-dose tadalafil can improve erectile function, increase penile blood flow velocity and alleviate clinical symptoms in ED patients with decline of vital gate fire, with definite clinical effect and safety.

Comparative Effectiveness of Lurbinectedin for the Treatment of Relapsed Small Cell Lung Cancer in the Post-Platinum Setting: A Real-World Canadian Synthetic Control Arm Analysis.

BACKGROUND: Based on findings from a single-arm, phase 2 basket trial (NCT02454972), lurbinectedin may be an effective treatment for individuals with small cell lung cancer (SCLC) who progressed on or after platinum-based chemotherapy. OBJECTIVE: To estimate the comparative effectiveness of lurbinectedin versus the historical standard of care for relapsed SCLC in Canada. METHODS: A synthetic control arm (SCA) analysis was conducted using real-world data. Population-level data were obtained from real-world databases in Alberta, Canada. Individuals diagnosed with SCLC who initiated post-platinum systemic therapy and met approximated eligibility criteria from the lurbinectedin trial were included in the SCA. Median overall survival (OS) in the SCA was estimated after adjusting for chemotherapy-free interval (CTFI; < 90 versus ≥ 90 days) and stage at initial diagnosis (extensive versus limited). The CTFI-adjusted hazard ratio was estimated using a Cox proportional hazards model. RESULTS: One hundred seventy-four individuals were included in the SCA and 105 in the lurbinectedin trial. The adjusted median OS in the SCA was 6.1 months (95% CI 5.4-7.7 months; unadjusted: 6.7 months, 95% CI 6.0-7.7 months) versus 9.3 months (95% CI 6.3-11.8 months) in the lurbinectedin trial. The adjusted hazard ratio comparing lurbinectedin with the historical standard of care (referent group) was 0.61 (95% CI 0.45-0.82; unadjusted HR: 0.72; 95% CI 0.54-0.97). The hazard ratio was more pronounced among individuals with CTFI ≥ 90 days (HR: 0.49, 95% CI 0.33-0.73). CONCLUSION: These findings suggest improved OS with lurbinectedin monotherapy versus the historical standard of care in Alberta, Canada.

Tetrahydro-ß-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity.

A series of tetrahydro-ß-carboline (THßC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THßC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.

Identification of 1,3,4-oxadiazolyl-containing ß-carboline derivatives as novel α-glucosidase inhibitors with antidiabetic activity.

In this study, we designed and synthesized a novel class of 1,3,4-oxadiazolyl-containing ß-carboline derivatives, i.e., compounds f1∼f35 as potential α-glucosidase inhibitors. All the synthesized compounds possessed outstanding α-glucosidase inhibitory activity with the IC50 values in the range of 3.07-15.49 µM, representing that they are 36∼183-fold more active than a positive control, acarbose (IC50 = 564.28 µM). Among them, compound f26 exhibited the highest α-glucosidase inhibitory activity (IC50 = 3.07 µM) and was demonstrated to function as a reversible and noncompetitive inhibitor. Mechanistic studies by means of 3D fluorescence spectra, CD spectra and molecular docking suggested that complexation of compound f26 with α-glucosidase through hydrogen bonds and hydrophobic interactions, led to changes in the conformation and secondary strictures of α-glucosidase and further the inhibition of the enzymatic activity. In vivo results showed that oral administration of compound f26 (50 mg/kg/day) could obviously reduce the levels of fasting blood glucose and improve glucose tolerance and dyslipidemia in diabetic mice. The present findings suggest that compound f26 is exploitable as a potential lead compound for the development of new α-glucosidase inhibitors with antidiabetic activity.

Rational design of ß-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy.

Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids ß-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.

Role of penile rehabilitation through daily intake of 5 mg tadalafil on erectile dysfunction after different presentations of penile fracture: a prospective case-control study.

PURPOSE: We aimed in the current study to identify the predictive factors of ED occurrence in healthy individuals following penile fracture surgical repair as well as the effect of penile rehabilitation in the form of daily tadalafil 5 mg intake for 1 month for patients who suffered from ED after penile fracture incident. METHOD: The current study was a prospective case-control study. Twenty-five patients were enrolled into the study starting from January (2022) to February (2023). Furthermore, time of presentation was determined, and length of tear intra-operative was measured, and then, a follow-up 1 week postoperatively in the outpatient clinic was conducted. All patients were instructed to start intercourse at least 2 weeks after the first visit provided that the wound epithelialized. Potent patients returned back home. A rehabilitation course of daily tadalafil 5 mg for 1 month was prescribed for patients who started complaining of ED that was confirmed by evaluation with the Arabic validated version of the international index of erectile function (ArIIEF-5). The rehabilitation therapy was terminated by resumption of normal erectile function. Thus, re-evaluation with the ArIIEF-5 was determined according to their response to therapy. Also, the patients were evaluated by hospital anxiety and depression scale (HADS) before and after penile fracture repair. RESULTS: The current study had demonstrated that a 1% increase in age determines an increase in odds ratio for post-penile fracture ED with 73.6% and 1 cm increase in the length of tear determines an increase in odds ratio for post-penile fracture ED with 20.04 times. CONCLUSION: The current study enhances the proper counseling of these patients prior to repairing the defect about the probability of ED occurrence as well as initiating early penile rehabilitation to help these patients resuming their normal sexual activity as soon as possible.

Improvement in Endothelial Function in Men Taking Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction.

BACKGROUND: The purpose of this research was to explore the mechanistic protective cardiovascular effects of phosphodiesterase-5 inhibitors (PDE5-Is) in males with erectile dysfunction. Erectile dysfunction and endothelial dysfunction both precede clinical atherosclerosis. Studies have shown that treatment for erectile dysfunction with PDE5-Is decreased death, heart failure, myocardial infarction, and revascularization in males with erectile dysfunction who had previous myocardial infarction, and cardiovascular events. METHODS: This was a pilot study that recruited 5 men with erectile dysfunction without cardiovascular disease. Endothelial function (flow-mediated percent change of the diameter of the brachial artery), erectile dysfunction grade, high-sensitivity C-reactive protein, and body mass index were measured before and 3 months after starting treatment with tadalafil, 5 mg daily. Pearson's analysis was performed to study a correlation between the change in erectile dysfunction and the change in endothelial function. RESULTS: A significant correlation was found between changes in flow-mediated percent change of the diameter of the brachial artery and changes in erectile dysfunction following the administration of tadalafil (P = .010; Pearson correlation coefficient = 0.959). No change was observed in C-reactive protein or weight. CONCLUSIONS: Erectile dysfunction and endothelial dysfunction are risk factors for cardiovascular disease. Our study showed that PDE5-Is improved endothelial function and erectile dysfunction (with a significant correlation). Improving endothelial function could be the mechanism that leads to a reduction in cardiovascular events and death in men with erectile dysfunction treated with PDE5-Is.

Synthesis and activity of ß-carboline antimalarials targeting the Plasmodium falciparum heat shock 90 protein.

A collection of ß-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds display promising bioactivity, providing a new potential therapeutic with a mode of action that differs versus any currently available clinical treatment.

Ferroptosis-Mediated Cell Death Induced by NCX4040, The Non-Steroidal Nitric Oxide Donor, in Human Colorectal Cancer Cells: Implications in Therapy.

Our recent studies show that the treatment of human ovarian tumor cells with NCX4040 results in significant depletions of cellular glutathione, the formation of reactive oxygen/nitrogen species and cell death. NCX4040 is also cytotoxic to several human colorectal cancer (CRC) cells in vitro and in vivo. Here, we examined the ferroptosis-dependent mechanism(s) of cytotoxicity of NCX4040 in HT-29 and K-RAS mutant HCT 116 colon cell lines. Ferroptosis is characterized by the accumulation of reactive oxygen species (ROS) within the cell, leading to an iron-dependent oxidative stress-mediated cell death. However, its relevance in the mechanism of NCX4040 cytotoxicity in CRCs is not known. We found that NCX4040 generates ROS in CRC cells without any depletion of cellular GSH. Combinations of NCX4040 with erastin (ER) or RSL3 (RAS-selective lethal 3), known inducers of ferroptosis, enhanced CRC death. In contrast, ferrostatin-1, an inhibitor of ferroptosis, significantly inhibited NCX4040-induced cell death. Treatment of CRC cells with NCX4040 resulted in the induction of lipid peroxidation in a dose- and time-dependent manner. NCX4040 treatment induced several genes related to ferroptosis (e.g., CHAC1, GPX4 and NOX4) in both cell lines. Metabolomic studies also indicated significant increases in both lipid and energy metabolism following the drug treatment in HT-29 and HCT 116 cells. These observations strongly suggest that NCX4040 causes the ferroptosis-mediated cell death of CRC cells. Furthermore, combinations of NCX4040 and ER or RSL3 may contribute significantly to the treatment of CRC, including those that are difficult to treat due to the presence of Ras mutations in the clinic. NCX4040-induced ferroptosis may also be a dynamic form of cell death for the treatment of other cancers.

ß-Carboline-α-aminophosphonate Derivative: A Promising Antitumor Agent for Breast Cancer Treatment.

Breast cancer is the most common type of cancer and the leading cause of cancer mortality among women worldwide. Considering the limitations of the current treatments available, we analyzed the in vitro cytotoxic potential of ((4-Fluoro-phenyl)-{2-[(1-phenyl-9H-ß-carboline-3-carbonyl)-amino]-ethylamino}-methyl)-phosphonic acid dibutyl ester (BCP-1) in breast cancer cells (MCF-7 and MDA-MB-231) and in a non-tumor breast cell line (MCF-10A). BCP-1 has an α-aminophosphonate unit linked to the ß-carboline nucleus, and the literature indicates that compounds of these classes have high biological potential. In the present study, the mechanism of action of BCP-1 was investigated through methods of spectrofluorimetry, flow cytometry, and protein expression analysis. It was found that BCP-1 inhibited the proliferation of both cancer cell lines. Furthermore, it induced oxidative stress and cell cycle arrest in G2/M. Upregulation of apoptosis-related proteins such as Bax, cytochrome C, and caspases, as well as a decrease in the anti-apoptotic protein Bcl-2, indicated potential induction of apoptosis in the MDA-MB-231 cells. While in MCF-7 cells, BCP-1 activated the autophagic death pathway, which was demonstrated by an increase in autophagic vacuoles and acidic organelles, in addition to increased expression of LC3I/LC3II and reduced SQSTM1/p62 expression. Further, BCP-1 demonstrated antimetastatic potential by reducing MMP-9 expression and cell migration in both breast cancer cell lines. In conclusion, BCP-1 is a promising candidate for breast cancer chemotherapy.

Macrophage-inherited exosome excise tumor immunosuppression to expedite immune-activated ferroptosis.

BACKGROUND: Immunosuppressive tumor microenvironment (ITM) remains an obstacle that jeopardizes clinical immunotherapy. METHODS: To address this concern, we have engineered an exosome inherited from M1-pheototype macrophages, which thereby retain functions and ingredients of the parent M1-phenotype macrophages. The delivered RSL3 that serves as a common ferroptosis inducer can reduce the levels of ferroptosis hallmarkers (eg, glutathione and glutathione peroxidase 4), break the redox homeostasis to magnify oxidative stress accumulation, promote the expression of ferroptosis-related proteins, and induce robust ferroptosis of tumor cells, accompanied with which systematic immune response activation can bbe realized. M1 macrophage-derived exosomes can inherit more functions and genetic substances than nanovesicles since nanovesicles inevitably suffer from substance and function loss caused by extrusion-arised structural damage. RESULTS: Inspired by it, spontaneous homing to tumor and M2-like macrophage polarization into M1-like ones are attained, which not only significantly magnify oxidative stress but also mitigate ITM including M2-like macrophage polarization and regulatory T cell decrease, and regulate death pathways. CONCLUSIONS: All these actions accomplish a synergistic antitumor enhancement against tumor progression, thus paving a general route to mitigate ITM, activate immune responses, and magnify ferroptosis.

Mitochondria-targeted cyclometalated iridium-ß-carboline complexes as potent non-small cell lung cancer therapeutic agents.

Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPßC)](PF6), where PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with ß-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.