Suppression of VEGF-induced angiogenesis and tumor growth by Eugenia jambolana, Musa paradisiaca, and Coccinia indica extracts

AbstractContext: Abnormal angiogenesis and evasion of apoptosis are hallmarks of cancer. Accordingly, anti-angiogenic and pro-apoptotic therapies are effective strategies for cancer treatment. Medicinal plants, namely, Eugenia jambolana Lam. (Myrtaceae), Musa paradisiaca L. (Musaceae), and Coccinia indica Wight & Arn. (Cucurbitaceae), have not been greatly investigated for their anticancer potential.Objective: We investigated the anti-angiogenic and pro-apoptotic efficacy of ethyl acetate (EA) and n-butanol (NB) extracts of E. jambolana (seeds), EA extracts of M. paradisiaca (roots) and C. indica (leaves) with respect to mammary neoplasia.Materials and methods: Effect of extracts (2–200 μg/mL) on cytotoxicity and MCF-7, MDA-MB-231 and endothelial cell (EC) proliferation and in vitro angiogenesis were evaluated by MTT, 3Hthymidine uptake and EC tube formation assays, respectively. In vivo tumour proliferation, VEGF secretion and angiogenesis were assessed using the Ehrlich ascites tumour (EAT) model followed by rat corneal micro-pocket and chicken chorioallantoic membrane (CAM) assays. Apoptosis induction was assessed by morphological and cell cycle analysis.Results: EA extracts of E. jambolana and M. paradisiaca exhibited the highest cytotoxicity (IC50 25 and 60 μg/mL), inhibited cell proliferation (up to 81\%), and tube formation (83\% and 76\%). In vivo treatment reduced body weight (50\%); cell number (16.5- and 14.7-fold), secreted VEGF (∼90\%), neoangiogenesis in rat cornea (2.5- and 1.5-fold) and CAM (3- and 1.6-fold) besides EAT cells accumulation in sub-G1 phase (20\% and 18.38\%), respectively.Discussion and conclusion: Considering the potent anti-angiogenic and pro-apoptotic properties, lead molecules from EA extracts of E. jambolana and M. paradisiaca can be developed into anticancer drugs

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Combinatorial treatment with anacardic acid followed by TRAIL augments induction of apoptosis in TRAIL resistant cancer cells by the regulation of p53, MAPK and NFκβ pathways

TRAIL, an apoptosis inducing cytokine currently in phase II clinical trial, was investigated for its capability to induce apoptosis in six different human tumor cell lines out of which three cell lines showed resistance to TRAIL induced apoptosis. To investigate whether Anacardic acid (A1) an active component of Anacardium occidentale can sensitize the resistant cell lines to TRAIL induced apoptosis, we treated the resistant cells with suboptimal concentration of A1 and showed that it is a potent enhancer of TRAIL induced apoptosis which up-regulates the expression of both DR4 and DR5 receptors, which has been observed in the cellular, protein and mRNA levels. The death receptors upregulation consequent to A1 treatment was corroborated by the activation of p53 as well as phosphorylation of p38 and JNK MAP kinases and concomitant inactivation of NFκβ and ERK signaling cascades. Also, A1 modulated the expression of key apoptotic players like Bax, Bcl-2 and CAD along with the abatement of tumor angiogenesis in vivo in EAT mouse model. Thus, post A1 treatment the TRAIL resistant cells turned into TRAIL sensitive cells. Hence our results demonstrate that A1 can synergize TRAIL induced apoptosis through the upregulation of death receptors and downregulation of anti-apoptotic proteins in cancer context

A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1

Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be ``addicted'' to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer. In the current study, we evaluated the efficacy of a pyrrole derivative bis(2-ethylhexyl)1H-pyrrole-3,4-dicarboxylate], TCCP, purified from leaves of Tinospora cordifolia for its ability to suppress heat shock response and angiogenesis using MDA-MB-231 cells and the murine mammary carcinoma: Ehrlich ascites tumor model. HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo-angiogenesis in vivo. The mechanism of suppression of HSPs involves inactivation of PI3K/Akt and phosphorylation on serine 307 of HSF-1 by the activation of ERK1. HSF-1 and HSP90 and 70 localization and expression were ascertained by immunolocalization, immunoblotting, and qPCR experiments. The anti-angiogenic effect of TCCP was studied in vivo in tumor-bearing mice and ex vivo using rat corneal micro-pocket assay. All the results thus corroborate the logic behind inactivating HSF-1 using TCCP as an alternative approach for cancer therapy

A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1

Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be ``addicted'' to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer. In the current study, we evaluated the efficacy of a pyrrole derivative bis(2-ethylhexyl)1H-pyrrole-3,4-dicarboxylate, TCCP, purified from leaves of Tinospora cordifolia for its ability to suppress heat shock response and angiogenesis using MDA-MB-231 cells and the murine mammary carcinoma: Ehrlich ascites tumor model. HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo-angiogenesis in vivo. The mechanism of suppression of HSPs involves inactivation of PI3K/Akt and phosphorylation on serine 307 of HSF-1 by the activation of ERK1. HSF-1 and HSP90 and 70 localization and expression were ascertained by immunolocalization, immunoblotting, and qPCR experiments. The anti-angiogenic effect of TCCP was studied in vivo in tumor-bearing mice and ex vivo using rat corneal micro-pocket assay. All the results thus corroborate the logic behind inactivating HSF-1 using TCCP as an alternative approach for cancer therapy

Synthesis and biological evaluation of novel isoxazolines linked via piperazine to 2- benzoisothiazoles as potent apoptotic agents

Synthesis of 3-(4-((3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl)piperazin-1-yl) benzoisothiazole derivatives (5a-i), which constitute a new class of isoxazolines, has been accomplished in regio-selective manner. These derivatives have been prepared by employing the reaction between substituted aldoximes (4a-i) and 3-(4-Allylpiperazin-1-yl) benzoisothiazole in presence of chloramine-T which afforded in good yields. These compounds were screened for cytotoxic activity on tumor cells. Four among the nine synthesized compounds were found to exhibit potent cytotoxic and antineoplastic activities in comparison to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) protein in mammalian cancer cells. The rest of the derivatives showed moderate activity