Annonaceae acetogenins: A potential treatment for gynecological and breast cancer.

Breast and gynecological cancers are major health concerns due to their increasing incidence rates, and in some cases, their low survival probability. In recent years, multiple compounds of natural origin have been analyzed as alternative treatments for this disease. For instance, Acetogenins are plant secondary metabolites from the Annonaceae family, and its potential anticancer activity has been reported against a wide range of cancer cells both in vitro and in vivo. Several studies have demonstrated promising results of Acetogenins' antitumor capacity, given their selective activity of cellular inhibition at low concentrations. This review outlines the origin, structure, and antineoplastic activities in vitro and in vivo of Acetogenins from Annonaceae against breast cancer and gynecological cancers reported to date. Here, we also provide a systematic summary of the activity and possible mechanisms of action of Acetogenins against these types of cancer and provide references for developing future therapies based on Acetogenins and nanotechnologies.

New Evidence on the Antiproliferative Activity of Campomanesia Adamantium (Cambess.) O. Berg Extracts in Melanoma Lung Metastasis.

Given the importance of discovering plant species from the Brazilian Cerrado biome with anticancer potential, this study evaluated the antitumor activity of two extracts of Campomanesi adamantium fruits in in vitro and in vivo models of melanoma lung metastasis. Pulp and peel extracts (DEGPU and DEGPE, respectively) were extracted from fresh fruit using dichloromethane as a solvent. As cytotoxicity parameter, concentration values that inhibited 50% cell growth (GI50), total growth inhibition (TGI), and selectivity index (SI) were established. The melanoma lung metastasis model was obtained by injecting 5 × 105/50 µL B16-F10 cells via the tail vein of mice, which received treatment on the 15th day. Metastatic lungs were collected for fluorescence analysis with the IR-780 marker and also macro- and microscopic assessment. In vitro analyses showed that DEGPU was active in K562 (GI50 32.99; TGI 47.93) and U-251 (GI50 32.10; TGI 249.92), whereas DEGPE showed better cytotoxicity results for all tumor cell lines, but was more efficient in K562 (GI50 27.42; TGI 40.20) and U-251 (GI50 4.89; TGI 12.77). Both showed a cytocidal effect on B16F10 at the highest concentration tested, with approximately 25% (DEGPU) and 88% (DEGPE) of cell death. In vivo analyzes showed that both extracts showed significant activity in metastatic lung. Fluorescence images showed differences in intensity between groups owing to greater tumor involvement. Macro- and microscopic images showed that treatments with extracts limited tumor growth and prevented proliferation. The extracts tested have promising activity, thus requiring further research on their active compounds.

Antitumoral Activity of Cecropia Pachystachya Leaves Extract in Vitro and in Vivo Model of Rat Glioma: Brain and Blood Effects.

The aim of this study was to investigate the antiglioma effect of Cecropia pachystachya Trécul (CEC) leaves extract against C6 and U87 glioblastoma (GB) cells and in a rat preclinical GB model. The CEC extract reduced in vitro cell viability and biomass. In vivo, the extract decreased the tumor volume approximately 62%, without inducing systemic toxicity. The deficit in locomotion and memory and an anxiolytic-like behaviors induced in the GB model were minimized by CEC. The extract decreased the levels of reactive oxygen species, nitrites and thiobarbituric acid reactive substances and increased the activity of antioxidant enzymes in platelets, sera and brains of GB animals. The activity of NTPDases, 5'-nucleotidase and adenosine deaminase (ADA) was evaluated in lymphocytes, platelets and serum. In platelets, ATP and AMP hydrolysis was reduced and hydrolysis of ADP and the activity of ADA were increased in the control, while in CEC-treated animals no alteration in the hydrolysis of ADP was detected. In serum, the reduction in ATP hydrolysis was reversed by CEC. In lymphocytes, the increase in the hydrolysis of ATP, ADP and in the activity of ADA observed in GB model was altered by CEC administration. The observed increase in IL-6 and decrease in IL-10 levels in the serum of GB animals was reversed by CEC. These results demonstrate that CEC extract is a potential complementary treatment to GB, decreasing the tumor size, while modulating aspects of redox and purinergic systems.

Avaliação morfológica e morfométrica do útero de camundongos fêmeas após uso de extrato de graviola / Morphological and morphometric evaluation of femal e mice uterus after using soursop extract

O presente estudo teve como objetivo avaliar o efeito do extrato de Annona muricata no útero de camundongos fêmeas por meio de análises macro e microscópicas. Vinte camundongos fêmeas foram aleatoriamente distribuídas em quatro grupos: controle (solução salina), ciclofosfamida e extrato de folhas de graviola em duas concentrações diferentes (50 e 100mg/kg). Após sete dias de experimento, as fêmeas foram eutanasiadas e seus úteros coletados e submetidos a análise macroscópica, seguida de processamento histológico para análises morfológicas e morfométricas das camadas do útero e das glândulas endometriais. As características macroscópicas do útero foram mantidas em todos os grupos avaliados. Microscopicamente, não foram identificadas alterações patológicas nas células uterinas. No entanto, houve um aumento significativo na camada do miométrio após o tratamento com ciclofosfamida (p<0,05). O diâmetro interno das glândulas endometriais foi significativamente menor em ambos os grupos tratados com extrato de A. muricata quando comparados ao grupo controle (p<0,05), enquanto o diâmetro total das glândulas foi significativamente menor somente na maior concentração de extrato de A. muricata quando comparado ao grupo controle (p<0,05). A administração do extrato de folhas de A. muricata não causou alterações morfológicas ao útero. Desta forma, o extrato não apresentou toxicidade uterina nas condições avaliadas.

O presente estudo teve como objetivo avaliar o efeito do extrato de Annona muricata no útero de camundongos fêmeas por meio de análises macro e microscópicas. Vinte camundongos fêmeas foram aleatoriamente distribuídas em quatro grupos: controle (solução salina), ciclofosfamida e extrato de folhas de graviola em duas concentrações diferentes (50 e 100mg/kg). Após sete dias de experimento, as fêmeas foram eutanasiadas e seus úteros coletados e submetidos a análise macroscópica, seguida de processamento histológico para análises morfológicas e morfométricas das camadas do útero e das glândulas endometriais. As características macroscópicas do útero foram mantidas em todos os grupos avaliados. Microscopicamente, não foram identificadas alterações patológicas nas células uterinas. No entanto, houve um aumento significativo na camada do miométrio após o tratamento com ciclofosfamida (p<0,05). O diâmetro interno das glândulas endometriais foi significativamente menor em ambos os grupos tratados com extrato de A. muricata quando comparados ao grupo controle (p<0,05), enquanto o diâmetro total das glândulas foi significativamente menor somente na maior concentração de extrato de A. muricata quando comparado ao grupo controle (p<0,05). A administração do extrato de folhas de A. muricata não causou alterações morfológicas ao útero. Desta forma, o extrato não apresentou toxicidade uterina nas condições avaliadas.

Brazilin: Biological activities and therapeutic potential in chronic degenerative diseases and cancer.

Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa).

Cervical cancer is the fourth leading cause of cancer mortality in women worldwide. Beetroot (Beta vulgaris L.) has bioactive compounds that can inhibit the progression of different types of cancer. To analyze the antiproliferative effects of beet leaf and root extracts, we performed MTT, clonogenic survival, cell cycle analysis, Annexin/PI labeling, and western blotting. Here, we report that 10 and 100 µg/ml of root and leaf extracts decreased cell viability and potentiated rapamycin and cisplatin effects while decreased the number of large colonies, especially at 10 µg/ml (293.6 of control vs. 200.0 of leaf extract, p = .0059; 138.6 of root extract, p = .0002). After 48 hr, 100 µg/ml of both extracts led to increased sub-G1 and G0/G1 populations. In accordance, 100 µg/ml of root extract induced early apoptosis (mean = 0.64 control vs. 1.56 root; p = .048) and decreased cell size (p < .0001). Both extracts decreased phosphorylation and expression of mechanistic Target of Rapamycin (mTOR) signaling, especially by inhibiting ribosomal protein S6 (S6) phosphorylation, increasing cleaved poly(ADP-ribose) polysomerase 1 (PARP1) and Bcl-2-like protein 11 (BIM), and decreasing cyclin D1 expression, which regulates cell cycle progression. Here, we demonstrate that beetroot and leaf extracts could be an efficient strategy against cervical cancer.

Resveratrol effects in oral cancer cells: a comprehensive review.

Oral cancer is a very common tumor worldwide with high incidence and mortality. The treatment of oral cancer involves surgery, radio- and chemotherapy; however, high failure rates and toxicity are noticed. Thus, the search of new drugs aiming a more effective treatment is welcomed. Natural products present chemopreventive and anti-cancer effects. Resveratrol is a naturally occurring antioxidant that contains several health benefits, including anti-inflammatory and antiproliferative activities. This review discusses the different action mechanisms of resveratrol related in the in vitro and in vivo studies using models of oral cancer.

Marine Seagrass Extract of Thalassia testudinum Suppresses Colorectal Tumor Growth, Motility and Angiogenesis by Autophagic Stress and Immunogenic Cell Death Pathways.

Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 µg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.

Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells.

Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction. In the present study, cytotoxic effects of several phenolic compounds against human the T-ALL cell line Jurkat were tested by means of resazurin-based metabolic assay. To unravel underlying mechanisms, mitochondrial membrane potential (∆Ψm) and [Ca2+]m measurements were undertaken, and reactive oxygen species generation and cell death were evaluated by flow cytometry. Three out of eight tested phenolics, cannabidiol, curcumin and quercetin, which displayed a significant cytotoxic effect, also dissipated the ∆Ψm and induced a significant [Ca2+]m increase, whereas inefficient phenols did not. Dissipation of the ∆Ψm by cannabidiol was prevented by cyclosporine A and reverted by Ru360, inhibitors of the permeation transition pore and mitochondrial Ca2+ uniporter, respectively. Ru360 prevented the phenol-induced [Ca2+]m rise, but neither cyclosporine A nor Ru360 affected the curcumin- and quercetin-induced ∆Ψm depolarization. Ru360 impeded the curcumin- and cannabidiol-induced cell death. Thus, all three phenols exert their antileukemic activity via mitochondrial Ca2+ overload, whereas curcumin and quercetin suppress the metabolism of leukemic cells by direct mitochondrial uncoupling.

The delay in cell death caused by the induction of autophagy by P2Et extract is essential for the generation of immunogenic signals in melanoma cells.

P2Et extract obtained from the Caesalpinia spinosa plant is abundant in phenolic compounds such as gallic acid and ethyl gallate and can generate signals to activate the immune response by inducing a mechanism known as immunogenic cell death in murine models of breast cancer and melanoma. Immunogenic cell death involves mechanisms such as autophagy, which can be modulated by various natural compounds, including phenolic compounds with a structure similar to those found in P2Et extract. Here, we determine the role of autophagy in apoptosis and the generation of immunogenic signals using murine wild-type B16-F10 melanoma cells and cells with beclin-1 gene knockout. We show that P2Et extract and ethyl gallate induced autophagy, partially protecting tumor cells from death and promoting calreticulin exposure and the release of ATP. Although ethyl gallate showed a mechanism similar to that of P2Et, the induction of apoptosis and immunogenic signals was significantly weaker. In contrast, gallic acid-induced autophagy acted by blocking autophagic flux, which was associated with increased cell death. However, this compound did not induce any of the immunogenic death signals evaluated. Therefore, the complex extract has greater antitumor potential than isolated compounds. Here, we show that inducing autophagic flux with P2Et protects cancer cells from cell death and that this delay in cell death is required for the generation of immunogenic signals.

Ethnopharmacology of Fruit Plants: A Literature Review on the Toxicological, Phytochemical, Cultural Aspects, and a Mechanistic Approach to the Pharmacological Effects of Four Widely Used Species.

Fruit plants have been widely used by the population as a source of food, income and in the treatment of various diseases due to their nutritional and pharmacological properties. The aim of this study was to review information from the most current research about the phytochemical composition, biological and toxicological properties of four fruit species widely used by the world population in order to support the safe medicinal use of these species and encourage further studies on their therapeutic properties. The reviewed species are: Talisia esculenta, Brosimum gaudichaudii, Genipa americana, and Bromelia antiacantha. The review presents the botanical description of these species, their geographical distribution, forms of use in popular medicine, phytochemical studies and molecules isolated from different plant organs. The description of the pharmacological mechanism of action of secondary metabolites isolated from these species was detailed and toxicity studies related to them were reviewed. The present study demonstrates the significant concentration of phenolic compounds in these species and their anti-inflammatory, anti-tumor, photosensitizing properties, among others. Such species provide important molecules with pharmacological activity that serve as raw materials for the development of new drugs, making further studies necessary to elucidate mechanisms of action not yet understood and prove the safety for use in humans.

The gastroprotective potential of silibinin against Helicobacter pylori infection and gastric tumor cells.

AIMS: Silibinin is the major component of flavonolignans complex mixture (Silymarin), which is obtained from Silybum marianum (L.) Gaertn. Despite several reports about silibinin, little is known about its effects on gastric diseases. Then, the present study aims to evaluate the silibinin effect against Helicobacter pylori infection, gastric tumor cells and immunomodulation. MAIN METHODS: The anti-H. pylori effect was performed on 43504 and 43629 strains by minimum inhibitory concentration (MIC) determination, observing morphological alterations by scanning electron microscopy and in silico evaluation by molecular docking. Immunomodulatory activity (Interleukins-6 and 10, TNF-α and NO inhibition) was determined in H. pylori-stimulated macrophages and the cytotoxic activity on gastric adenocarcinoma cells prior and after metabolization by S9 fraction. KEY FINDINGS: Silibinin showed anti-H. pylori activity with MIC of 256 µg/mL, promoted important morphological changes in the bacterial cell wall, as blebs and clusters, suggesting interaction with Penicillin Binding Protein (PBP) subunits. Immunomodulatory potential was observed at 50 µg/mL with the inhibition of produced cytokines and NO by H. pylori-stimulated macrophages of 100% for TNF-ɑ, 56.83% for IL-6, and 70.29% for IL-10 and 73.33% for NO. Moreover, silibinin demonstrated significant cytotoxic activity on adenocarcinoma cells (CI50: 60.17 ± 0.95 µg/mL) with a higher selectivity index (SI: 1.52) compared to cisplatin. After metabolization silibinin showed an increase of cytotoxicity with a CI50 six-fold decrease (10.46 ± 0.25). SIGNIFICANCE: The use of silibinin may become an important alternative tool in the prevention and treatment of H. pylori infection and, consequently, in gastric cancer.

Vincristine and ivermectin combination chemotherapy in dogs with natural transmissible venereal tumor of different cyto-morphological patterns: A prospective outcome evaluation.

Vincristine is the first-line drug for the chemotherapy of canine transmissible venereal tumor (CTVT). Drug resistance is related to tumor cyto-morphological patterns of CTVT. There are anti-cancer properties of ivermectin, thus, a combination of ivermectin and vincristine could be an effective chemo-therapeutic treatment regimen for CTVT. Study aims, therefore, were to (1) assess the frequency of CTVT cyto-morphologies, and (2) evaluate treatment efficacy and possible adverse reactions to vincristine compared with a combination vincristine and ivermectin. Dogs (n = 41) with CTVT were characterized by tumor cyto-morphology and disease severity and of those, 20 were randomly allocated into two groups. There was a control group (G-Vin; n = 10) in which there was treatment with vincristine; and an experimental group (G-Iv/Vin; n = 10) in which there was treatment with the ivermectin/vincristine combination. Although dogs in the G-Iv/Vin group had more severe disease at the beginning of the study (P = 0.0031), the number of weeks and chemotherapy sessions until tumor remission were similar among dogs of the two groups, indicating both treatments were effective. There was a decrease in the leukocyte counts (P = 0.0020), related to neutropenia (P = 0.0371) in the G-Vin but not the G-Iv/Vin treatment group. There was no tumor resistance that developed during the study regardless of the treatment regimen used or tumor cytomorphology. In summary, the use of the vincristine/ivermectin combination was well tolerated and efficacious for CTVT treatment.

Early Progression and Immune Reconstitution Inflammatory Syndrome During Treatment of Mild-To-Moderate Kaposi Sarcoma in Sub-Saharan Africa and South America: Incidence, Long-Term Outcomes, and Effects of Early Chemotherapy.

BACKGROUND: Early progression of AIDS-associated Kaposi sarcoma (KS-PD) and immune reconstitution inflammatory syndrome (KS-IRIS) sometimes occur after the initiation of antiretroviral therapy (ART). METHODS: Early KS-PD and KS-IRIS were assessed in the A5264/AMC-067 trial in which participants with mild-to-moderate AIDS-KS were randomized to initiate ART with either immediate or as-needed oral etoposide. Early KS-PD was defined as tumor progression within 12 weeks of ART initiation. When investigators had concern that early KS-PD was KS-IRIS, additional evaluations were performed. Suspected KS-IRIS was defined as early KS-PD accompanied by a CD4 count increase of ≥50 cells per cubic millimeter or plasma HIV-1 RNA decrease of ≥0.5 log10 copies/mL. Clinical outcome was a composite end point categorized as failure, stable, and response at 48 and 96 weeks compared with baseline. RESULTS: Fifty of 190 participants had early KS-PD (27%): 28 had KS-IRIS and 22 were not evaluated for KS-IRIS. Early KS-PD and KS-IRIS incidences with immediate etoposide versus ART alone were 16% versus 39%, and 7% versus 21%, respectively. Week 48 clinical outcome was 45% failure, 18% stable, and 37% response for no early KS-PD; 82% failure, 2% stable, and 16% response for early KS-PD; and 88% failure, 0% stable, and 12% response for KS-IRIS. Cumulative incidence of KS tumor response by week 96 was 64% for no early KS-PD, 22% with early KS-PD, and 18% with KS-IRIS. CONCLUSIONS: Early KS-PD, including suspected KS-IRIS, was common after starting ART for AIDS-KS and was associated with worse long-term clinical outcomes. Starting ART concurrently with etoposide reduced the incidence of both early KS-PD and KS-IRIS compared with ART alone.

Long-term survival of a patient with an inoperable thymic neuroendocrine tumor stage IIIa under sole treatment with Viscum album extract: A CARE compliant clinical case report.

RATIONALE: Thymic neuroendocrine tumor (TNET) is very rare and characterized by a tendency to invade adjacent structures, frequent metastasis, resistance to therapy, and a poor prognosis. Viscum album extracts (VAE) have shown immunological, apoptogenic, and cytotoxic properties. PATIENT CONCERNS: A 54-year-old Peruvian man was suffering from constant fatigue, cough, dyspnea, and fever for a couple of months. DIAGNOSES: He was diagnosed with TNET (12.8 cm × 10 cm × 7 cm) stage IIIa, G1. Due to the size and extensive invasiveness (vena cava superior, also obstructing 85% of its lumen, pericardium, and pleura), the TNET was inoperable. INTERVENTIONS: We report the case of this patient who declined chemotherapy and was treated instead with sole subcutaneous VAE 3 times per week for 85 months. No other tumor-specific intervention was applied. OUTCOMES: Quality of life (QoL) improved substantially. The patient returned to work, and the tumor remained stable for 71 months. Thereafter, the tumor progressed, and the patient died 90 months after initial diagnosis. Besides self-limited local skin reactions around the application site, no side effects occurred. LESSONS: This is an exceptionally good course of disease of an inoperable, large, obstructing, and invasive TNET with a reduced baseline condition (Karnofsky index: 50-60) due to pronounced symptoms. Given the considerable reduction of symptoms and improved QoL following the onset of VAE therapy and other reports describing long disease stability and improvement of the QoL using VAE in different cancer types, we presume that the VAE treatment was supportive in this case. As TNETs are rare and few trials are available, future treatments of TNETs using VAE should be carefully documented and published to help determine whether further investigation of the use of VAE in TNET treatment is worthwhile.

Matteucinol, isolated from Miconia chamissois, induces apoptosis in human glioblastoma lines via the intrinsic pathway and inhibits angiogenesis and tumor growth in vivo.

Gliomas account for nearly 70% of the central nervous system tumors and present a median survival of approximately 12-17 months. Studies have shown that administration of novel natural antineoplastic agents is been highly effective for treating gliomas. This study was conducted to investigate the antitumor potential (in vitro and in vivo) of Miconia chamissois Naudin for treating glioblastomas. We investigated the cytotoxicity of the chloroform partition and its sub-fraction in glioblastoma cell lines (GAMG and U251MG) and one normal cell line of astrocytes. The fraction showed cytotoxicity and was selective for tumor cells. Characterization of this fraction revealed a single compound, Matteucinol, which was first identified in the species M. chamissois. Matteucinol promoted cell death via intrinsic apoptosis in the adult glioblastoma lines. In addition, Matteucinol significantly reduced the migration, invasion, and clonogenicity of the tumor cells. Notably, it also reduced tumor growth and angiogenesis in vivo. Moreover, this agent showed synergistic effects with temozolomide, a chemotherapeutic agent commonly used in clinical practice. Our study demonstrates that Matteucinol from M chamissois is a promising compound for the treatment of glioblastomas and may be used along with the existing chemotherapeutic agents for more effective treatment.

Systematic review and meta-analysis of docetaxel perioperative chemotherapy regimens in gastric and esophagogastric tumors.

FLOT regimen became the standard perioperative treatment in several centers around the world for esophagogastric tumors despite concerns about toxicity. In addition, FLOT has never been compared with other docetaxel-based regimens. To address this question, we conducted a systematic review of PubMed, Embase and Web of Science including prospective or retrospective studies of docetaxel based perioperative regimen in gastric and esophagogastric tumors. Data regarding chemotherapy regimens, efficacy and toxicity were extracted. Outcomes were compared using a random effects model. Of 548 abstracts, 16 were considered eligible. Comparing the studies with meta-analysis we can see that the regimens are similar in terms of pathological complete response, resection rate, progression free survival and overall survival in one year, without significant heterogeneity. The meta-regression of docetaxel dose failed to show any association with dose ranging between 120-450 mg/m². Regarding the toxicity of the regimens it is noted that the regimens are quite toxic (up to 50-70% of grade 3-4 neutropenia). The results of this meta-analysis with a combined sample size of more than 1,000 patients suggest that docetaxel perioperative regimens are equivalent in outcomes. Prospective trials addressing modified regimens should be performed to provide less toxic strategies and be applicable to all patients.

The role of the multi-drug resistance 1, p53, b cell lymphoma 2, and bcl 2-associated X genes in the biologic behavior and chemotherapeutic resistance of canine transmissible venereal tumors.

BACKGROUND: Canine transmissible venereal tumors (CTVTs) generally have different cytomorphologic subtypes and phases of progression. Some tumors have variable biologic behavior including a progressive increase in tumor aggressiveness and variable responses to chemotherapy. This behavior is partially due to high p-glycoprotein expression by tumor cells, which leads to the expulsion of chemotherapeutic drugs. Other possible causes include changes in pro- and anti-apoptotic genes from the BCL-2 family and DNA repair systems, which are associated with the p53 gene family. OBJECTIVES: We aimed to determine the relative expression of the multi-drug resistance 1 (MDR1), p53, b-cell lymphoma 2 (BCL2), and bcl 2-associated X (BAX) genes in CTVT before and after therapy and establish a relationship with treatment responses, cytomorphologic patterns, and tumor progression identified with histopathology. METHODS: RT-qPCR was performed on 21 CTVT tumor samples before and after initiating chemotherapy to determine specific gene expression. Normal canine testicular tissue was used as a negative control for all experiments. RESULTS: MDR1 expression was decreased before and after initiating vincristine therapy in CTVT tumor tissues compared with normal canine testicular tissue; p53 and BAX were overexpressed at both time points compared with normal tissue, and no statistical differences were seen between the different morphologic types. However, BAX expression was decreased in the group with quick therapeutic responses but was still overexpressed compared with normal testicular tissue. In the group with the slowest chemotherapeutic responses, BCL2 was overexpressed. CONCLUSION: The findings of this study showed a relative increase in MDR1 gene expression in response to chemotherapy and higher expression in plasmacytoid CTVTs compared with the other cytomorphologic patterns. BCL2 overexpression was related to a favorable prognosis, and p53, BAX, and BCL2 were expressed independent of the cytomorphologic CTVT type. All of the genes were expressed independent of tumor progression, as noted on histopathology.

Upregulation of miR-129-5p increases the sensitivity to Taxol through inhibiting HMGB1-mediated cell autophagy in breast cancer MCF-7 cells.

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.

Caracasine acid, an ent-3,4-seco-kaurene, promotes apoptosis and cell differentiation through NFkB signal pathway inhibition in leukemia cells.

Caracasine acid (CA) is an ent-3,4-seco-kaurene isolated from the plant Croton micans. Decreased cancer cell lines viability was reported upon CA treatment. The present study aimed to investigate the mechanism of CA induced cytotoxicity using two human cell lines, Jurkat E6.1 (human cell T lymphoma) and HL-60 (human acute promyelocytic leukemia). Significant increases of apoptotic cell death markers upon CA treatment were observed: annexin-V positiveness, potential mitochondrial disturbances, cell cycle changes, caspase activation, and CD95 expression. These effects were not detected in normal lymphocytes. CA induced the appearance of Bax, cleaved caspase 3, and cytochrome c release in Jurkat cells, and cleaved caspase 3 and phosphorylated p53 in HL60 cells. Likewise, downregulation of anti-apoptotic proteins such as Bcl-x (Jurkat), Bcl-2, and XIAP (HL60) was observed with CA treatment. Both pathways, intrinsic and extrinsic were activated when cell lines were treated with CA. NF-κB p65 inhibition was observed in Jurkat cells and cell differentiation in HL-60 cells. CA could be a potential leader compound for the development of new drugs for leukemia treatment in humans.