The Cancer-Protective Potential of Protocatechuic Acid: A Narrative Review.

Cancer is one of the leading causes of death worldwide, making the search for alternatives for its control a critical issue. In this context, exploring alternatives from natural sources, such as certain vegetables containing a variety of secondary metabolites with beneficial effects on the body and that play a crucial role in the fight against cancer, is essential. Among the compounds with the greatest efficacy in controlling this disease, those with antioxidant activity, particularly phenolic com-pounds, stand out. A remarkable example of this group is protocatechuic acid (PCA), which has been the subject of various revealing research on its activities in different areas. These studies sustain that protocatechuic acid has anti-inflammatory, antimutagenic, antidiabetic, antiulcer, antiviral, antifibrogenic, antiallergic, neuroprotective, antibacterial, anticancer, antiosteoporotic, anti-aging, and analgesic properties, in addition to offering protection against metabolic syndrome and con-tributing to the preservation of hepatic, renal, and reproductive functionality. Therefore, this paper aims to review the biological activities of PCA, focusing on its anticancer potential and its in-volvement in the control of various molecular pathways involved in tumor development, sup-porting its option as a promising alternative for cancer treatment.

Role of SIRT1 in Chemoresistant Leukemia.

Leukemias of the AML, CML, and CLL types are the most common blood cancers worldwide, making them a major global public health problem. Furthermore, less than 24% of patients treated with conventional chemotherapy (low-risk patients) and 10-15% of patients ineligible for conventional chemotherapy (high-risk patients) survive five years. The low levels of survival are mainly due to toxicity and resistance to chemotherapy or other medication, the latter leading to relapse of the disease, which is the main obstacle to the treatment of leukemia. Drug resistance may include different molecular mechanisms, among which epigenetic regulators are involved. Silent information regulator 2 homolog 1 (SIRT1) is an epigenetic factor belonging to the sirtuin (SIRT) family known to regulate aspects of chromatin biology, genome stability, and metabolism, both in homeostasis processes and in different diseases, including cancer. The regulatory functions of SIRT1 in different biological processes and molecular pathways are dependent on the type and stage of the neoplasia; thus, it may act as both an oncogenic and tumor suppressor factor and may also participate in drug resistance. In this review, we explore the role of SIRT1 in drug-resistant leukemia and its potential as a therapeutic target.

Effect of Resveratrol on Markers of Oxidative Stress and Sirtuin 1 in Elderly Adults with Type 2 Diabetes.

Type 2 diabetes (T2D) affects a large part of the adult population and impairs its quality of life. Because of this, natural compounds with antioxidant, anti-inflammatory and hypoglycemic properties have been used as adjuvants. Among these compounds, resveratrol (RV) stands out, a polyphenol that has been studied in several clinical trials, the results of which are controversial. We conducted a randomized clinical trial on 97 older adults with T2D to evaluate the effect of RV on oxidative stress markers and sirtuin 1, using doses of 1000 mg/day (EG1000, n = 37) and 500 mg/day (EG500, n = 32) compared with a placebo (PG, n = 28). Biochemical markers, oxidative stress and sirtuin 1 levels were measured at baseline and after six months. We observed a statistically significant increase (p < 0.05) in total antioxidant capacity, antioxidant gap, the percentage of subjects without oxidant stress and sirtuin 1 levels in EG1000. In the PG, we observed a significant increase (p < 0.05) in lipoperoxides, isoprostanes and C-reactive protein levels. An increase in the oxidative stress score and in the percentage of subjects with mild and moderate oxidative stress was observed too. Our findings suggest that 1000 mg/day of RV exerts a more efficient antioxidant effect than 500 mg/day.

Influence of Age and Dose on the Effect of Resveratrol for Glycemic Control in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis.

Background: Several clinical trials have suggested that resveratrol has hypoglycemic properties; however, there are other studies in which such an effect has not been observed. Methods: We carried out a systematic search in several databases; seventeen studies were selected for the systematic review and fifteen were included in the meta-analysis. Results: Resveratrol decreases glucose levels in subjects aged 45−59 years at doses <250 mg/day (−8.64 mg/dL, p < 0.00001), 250−500 mg/day (−22.24 mg/dL, p = 0.0003), and 500−1000 mg/day (−28.40 mg/dL, p = 0.0008), while in subjects older than 60 years, it only decreases with doses of 250−500 mg/day. Likewise, HbA1c improved in subjects aged 45−59 years with doses of 250−500 mg (−0.60%, p < 0.00001), but not in subjects older than 60 years. Insulin levels improved in subjects aged 45−59 years with doses < 250 mg/day (−0.80 mIU/L, p = 0.0003) and doses of 250−500 mg/day (−5.0 mIU/L, p = 0.0003), although in subjects older than 60 years, they only improved with doses of 250−500 mg/day (−1.79 mIU/L, p = 0.01). On the other hand, HOMA-IR only improved in subjects older than 60 years with doses of 250−500 mg/day (−0.40, p = 0.01). Conclusions: Resveratrol has a statistically significant dose−response effect on glucose concentrations, HbA1c, and insulin levels; however, there is not enough scientific evidence to propose a therapeutic dose.

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review.

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

Phytochemical Analysis and Antioxidant and Anti-Inflammatory Capacity of the Extracts of Fruits of the Sechium Hybrid.

In addition to their own antioxidants, human cells feed on external antioxidants, such as the phenolic compounds of fruits and vegetables, which work together to keep oxidative stress in check. Sechium edule, an edible species of chayote, has phenolic compounds with antioxidant activity and antineoplastic activity. A Sechium hybrid shows one thousand times greater antineoplastic activity than edible species, but its antioxidant and anti-inflammatory activities and the content of phenolic compounds are unknown. The aim of this study was to determine the antioxidant and anti-inflammatory capacity of the extract of fruits of the Sechium hybrid in vitro and in vivo. Phytochemical analysis using HPLC showed that the extract of the Sechium hybrid has at least 16 phenolic compounds; galangin, naringenin, phloretin and chlorogenic acid are the most abundant. In an in vitro assay, this extract inhibited 2,2-diphenyl-L-picrylhydrazyl (DPPH) activity and protected the dimyristoylphosphatidylethanolamine (DMPE) phospholipid model cell membrane from oxidation mediated by hypochlorous acid (HClO). In vivo, it was identified that the most abundant metabolites in the extract enter the bloodstream of the treated mice. On the other hand, the extract reduces the levels of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin-6 (IL-6) but increases interleukin-10 (IL-10) and glutathione peroxidase levels. Our findings indicate that intake of the fruits of the Sechium hybrid leads to antioxidant and anti-inflammatory effects in a mouse model. Therefore, these results support the possibility of exploring the clinical effect of this hybrid in humans.

Mesenchymal Stem Cells of Dental Origin for Inducing Tissue Regeneration in Periodontitis: A Mini-Review.

Periodontitis is a chronic disease that begins with a period of inflammation of the supporting tissues of the teeth table and then progresses, destroying the tissues until loss of the teeth occurs. The restoration of the damaged dental support apparatus is an extremely complex process due to the regeneration of the cementum, the periodontal ligament, and the alveolar bone. Conventional treatment relies on synthetic materials that fill defects and replace lost dental tissue, but these approaches are not substitutes for a real regeneration of tissue. To address this, there are several approaches to tissue engineering for regenerative dentistry, among them, the use of stem cells. Mesenchymal stem cells (MSC) can be obtained from various sources of adult tissues, such as bone marrow, adipose tissue, skin, and tissues of the orofacial area. MSC of dental origin, such as those found in the bone marrow, have immunosuppressive and immunotolerant properties, multipotency, high proliferation rates, and the capacity for tissue repair. However, they are poorly used as sources of tissue for therapeutic purposes. Their accessibility makes them an attractive source of mesenchymal stem cells, so this review describes the field of dental stem cell research and proposes a potential mechanism involved in periodontal tissue regeneration induced by dental MSC.

Chemical analyses and in vitro and in vivo toxicity of fruit methanol extract of Sechium edule var. nigrum spinosum.

CONTEXT: Sechium edule (Jacq.) Sw. (Cucurbitaceae) is used in ethnomedicine, but the diversity of the varietal groups of this species has not often been considered. This is important because we previously reported that different variety of species exhibit different activities across different tumor cell lines. OBJECTIVE: This study investigates the chemical composition and biological activities of extracts obtained from S. edule var. nigrum spinosum. MATERIALS AND METHODS: The leukemia P388 cell line and mononuclear bone marrow cells (MNCBMs) were treated with the extract at a concentration ranging from 40 to 2370 µg/mL for cytotoxicity and viability assays. CD-1 mice were treated with 8-5000 mg/kg extract and monitored every hour for the first 24 h and subsequently for seven days for signs of toxicity (LD50). In addition, the chromatographic profile of the extract was determined by HPLC. RESULTS: The extract inhibits the proliferation of both P388 cells and MNCBMs, with IC50 values of 927 and 1911 µg/mL, respectively, but reduced the viability and induced the apoptosis of only leukemia cells. The LD50 was higher than 5000 mg/kg, and this concentration did not alter the blood chemistry or cell count but doubled the mitotic index in the bone marrow. The HPLC showed the presence of cucurbitacins, phloridzin, naringenin, phloretin, apigenin, and gallic, chlorogenic, vanillic, p-hydroxybenzoic, caffeic, and p-coumaric acids. DISCUSSION AND CONCLUSION: Sechium edule var. nigrum spinosum contains bioactive compounds that explain the antiproliferative and nutraceutical activities, and its lack of physiological side effects constitutes an added value to a widely consumed vegetable.

Fruit extract from a Sechium edule hybrid induce apoptosis in leukaemic cell lines but not in normal cells.

The antiproliferative potential of a crude extract from the chayote hybrid H-837-07-GISeM® and its potential for apoptosis induction were assessed in leukaemic cell lines and normal mouse bone marrow mononuclear cells (BM-MNCs). The extract strongly inhibited the proliferation of the P388, J774, and WEHI-3 cell lines (with an IC50 below 1.3 µg·mL(-1)), reduced cell viability, and induced apoptotic body production, phosphatidylserine translocation, and DNA fragmentation. However, the extract had no effect on BM-MNCs. We postulate that these properties make the extract a good candidate for an anti-tumour agent for clinical use.

Immunization with an HPV-16 L1-based chimeric virus-like particle containing HPV-16 E6 and E7 epitopes elicits long-lasting prophylactic and therapeutic efficacy in an HPV-16 tumor mice model.

HPV L1-based virus-like particles vaccines (VLPs) efficiently induce temporary prophylactic activity through the induction of neutralizing antibodies; however, VLPs that can provide prophylactic as well as therapeutic properties for longer periods of time are needed. For this purpose, we generated a novel HPV 16 L1-based chimeric virus-like particle (cVLP) produced in plants that contains a string of T-cell epitopes from HPV 16 E6 and E7 fused to its C-terminus. In the present study, we analyzed the persistence of specific IgG antibodies with neutralizing activity induced by immunization with these cVLPs, as well as their therapeutic potential in a tumor model of C57BL/6 mice. We observed that these cVLPs induced persistent IgG antibodies for over 12 months, with reactivity and neutralizing activity for VLPs composed of only the HPV-16 L1 protein. Efficient protection for long periods of time and inhibition of tumor growth induced by TC-1 tumor cells expressing HPV-16 E6/E7 oncoproteins, as well as significant tumor reduction (57 %), were observed in mice immunized with these cVLPs. Finally, we discuss the possibility that chimeric particles of the type described in this work may be the basis for developing HPV prophylactic and therapeutic vaccines with high efficacy.

Anti-cancer potential of casein and its derivatives: novel strategies for cancer treatment.

Cancer is one of the leading causes of death worldwide, with over 10 million fatalities annually. While tumors can be surgically removed and treated with chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or combined therapies, current treatments often result in toxic side effects in normal tissue. Therefore, researchers are actively seeking ways to selectively eliminate cancerous cells, minimizing the toxic side effects in normal tissue. Caseins and its derivatives have shown promising anti-cancer potential, demonstrating antitumor and cytotoxic effects on cells from various tumor types without causing harm to normal cells. Collectively, these data reveals advancements in the study of caseins and their derivative peptides, particularly providing a comprehensive understanding of the molecular mechanism of action in cancer therapy. These mechanisms occur through various signaling pathways, including (i) the increase of interferon-associated STAT1 signaling, (ii) the suppression of stemness-related markers such as CD44, (iii) the attenuation of the STAT3/HIF1-α signaling, (iv) the down-expression of uPAR and PAI-1, (v) the loss of mitochondrial membrane potential and reduced intracellular ATP production, (vi) the increase of caspase-3 activity, and (vii) the suppression of TLR4/NF-кB signaling. Therefore, we conclude that casein could be an effective adjuvant for cancer treatment.

Antineoplastic Activity of Sodium Caseinate in a Cytarabine-Resistant Mouse Acute Myeloid Leukemia Cell Line.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological neoplasm of rapid and progressive onset, and is the most common form of leukemia in adults. Chemoresistance to conventional treatments such as cytarabine (Ara-C) and daunorubicin is a main cause of relapse, recurrence, metastasis, and high mortality in AML patients. It is known that sodium caseinate (SC), a salt derived from casein, a milk protein, inhibits growth and induces apoptosis in acute myeloid leukemia cells but not in normal hematopoietic cells. However, it is unknown whether SC retains its antileukemic effect in cytarabine-resistant AML cell lines. OBJECTIVE: To evaluate the antineoplastic effect of SC in cytarabine-resistant leukemia models. METHODS: The SC inhibits the growth and induces apoptosis in parental WEHI-3 AML cells. Here, we generated two cytarabine-resistant sublines, WEHI-CR25 and WEHI-CR50, which exhibit 6- and 16-fold increased resistance to cytarabine, respectively, compared to the parental WEHI-3 cells. Thus, these sublines mimic a chemoresistant model. RESULTS: We demonstrate that WEHI-CR25 and WEHI-CR50 cells retain sensitivity to SC, similar to parental WEHI-3 cells. This sensitivity results in inhibited cell proliferation, induced apoptosis, and increased expression of ENT1 and dCK, molecules involved in the entry and metabolism of Ara-C, while decreasing MDR1 expression. Additionally, we observed that SC prolonged the survival of WEHI-CR50 tumor-bearing mice, despite their resistance to Ara-C. CONCLUSION: This is the first evidence that SC, a milk protein, may inhibit proliferation and induce apoptosis in cytarabine-resistant cells.

The Supplementation of Sechium edule var. nigrum spinosum (Chayote) Promotes Nrf2-Mediated Antioxidant Protection in Older Adults with Metabolic Syndrome.

The aim was to determine the effect of Sechium edule var. nigrum spinosum (chayote) on gene expression related to antioxidant protection mechanisms and the inflammatory process in older adults with metabolic syndrome (MetS). A quasi-experimental study was carried out in a convenience sample of 46 older adults diagnosed with MetS: (i) placebo group (PG; n = 20); (ii) experimental group (EG; n = 26). The clinical, biochemical, anthropometric parameters and SOD, GPx, and CAT enzyme activity, alongside total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), cytokines (IL-6, IL-8 and TNF-α), and mRNA expression of SOD, GPx, CAT, IL-6, IL-8, TNF-α, Nrf2, NFkB p50, and NFkB p65, were measured at baseline and 6 months post-intervention. A statistically significant decrease was observed in TOS (baseline, 28.9 ± 3.6 vs. post, 23.7 ± 3.4, p < 0.01) and OSI (baseline, 24.1 ± 3.8 vs. post, 17.7 ± 4), as well as an increase in IL-6 (baseline, 10.7 ± 1.1 vs. post, 12.3 ± 2, p = 0.03), SOD activity (baseline, 167.1 ± 11.9 vs. post, 180.6 ± 7.6, p < 0.05), CAT activity (baseline, 1.0 ± 0.2 vs. post, 1.3 ± 0.2, p < 0.01), and TAS (baseline, 1.1 ± 0.1 vs. post, 1.4 ± 0.1, p < 0.01) in the EG compared to the PG. Regarding the expression of Nrf2, SOD, and IL-6, the EG showed a significant increase vs. basal levels (47%, 44%, and 43%, respectively). Our findings suggest that Sechium edule supplementation promotes the antioxidant response and decreases oxidative stress via Nrf2.

Aging, Physical Exercise, Telomeres, and Sarcopenia: A Narrative Review.

Human aging is a gradual and adaptive process characterized by a decrease in the homeostatic response, leading to biochemical and molecular changes that are driven by hallmarks of aging, such as oxidative stress (OxS), chronic inflammation, and telomere shortening. One of the diseases associated with the hallmarks of aging, which has a great impact on functionality and quality of life, is sarcopenia. However, the relationship between telomere length, sarcopenia, and age-related mortality has not been extensively studied. Moderate physical exercise has been shown to have a positive effect on sarcopenia, decreasing OxS and inflammation, and inducing protective effects on telomeric DNA. This results in decreased DNA strand breaks, reduced OxS and IA, and activation of repair pathways. Higher levels of physical activity are associated with an apparent increase in telomere length. This review aims to present the current state of the art of knowledge on the effect of physical exercise on telomeric maintenance and activation of repair mechanisms in sarcopenia.

The consumption of Sechium edule (chayote) has antioxidant effect and prevents telomere attrition in older adults with metabolic syndrome.

OBJECTIVE: To determine the effect of the consumption of Sechium edule (1.5 g/day) for six months on oxidative stress (OxS) and inflammation markers and its association with telomere length (TL) in older adults with metabolic syndrome (MetS). METHODS: The study was conducted in a sample of 48 older adults: placebo (EP) and experimental (EG) groups. Lipoperoxides, protein carbonylation, 8-OHdG, total oxidant status (TOS), SOD, GPx, H2O2 inhibition, total antioxidant status (TAS), inflammatory cytokines (IL6, IL10, TNF-α), and TL were measured before and six months post-treatment. RESULTS: We found a significant decrease in the levels of lipoperoxides, protein carbonylation, 8-OHdG, TOS in the EG in comparison PG. Likewise, a significante increase of TAS, IL-6, and IL-10 levels was found at six months post-treatment in EG in comparison with PG. TL showed a statistically significant decrease in PG compared to post-treatment EG. CONCLUSIONS: Our findigns showed that the supplementation of Sechium edule has antioxidant, and anti-inflammatory effects, and diminushion of shortening of telomeric DNA in older adults with MetS. This would be the first study that shows that the intervention with Sechium edule has a possible geroprotective effect by preventing telomeres from shortening as usually happens in these patients. Therefore, suggesting a protection of telomeric DNA and genomic DNA.

Fruit Extract of Sechium chinantlense (Lira & F. Chiang) Induces Apoptosis in the Human Cervical Cancer HeLa Cell Line.

Sechium edule (Cucurbitaceae) is a commercial species of chayote and is just one of several species in the genus Sechium, whose extracts inhibit proliferation in tumor cell lines. The capacity of the wild species Sechium chinantlense (SCH) as an antitumor agent is unknown, as is the mechanism of action. In the present study, HeLa cervical cancer and HaCaT normal cell lines were treated with SCH and cell proliferation was inhibited in both cell lines in a dose-dependent manner similar to the effect of the antineoplastic agent cisplatin (Cis). Additionally, SCH arrested cell cycle progression but only in HeLa cells and induced apoptosis, as shown by phosphatidylserine translocation and caspase-3 activation, while Cis did so in both cell lines. Exploration of the mechanism of action of SCH in HeLa cells suggests that apoptosis was mediated by the intrinsic signaling pathway since there was no activation of caspase-8, but there was a release of cytochrome-c. These findings suggest that the SCH extract has the potential to selectively kill tumor cells by promoting apoptosis, without harming nontumor cells.

Sodium caseinate induces mouse granulopoiesis.

OBJECTIVE AND DESIGN: Sodium caseinate (CasNa) induces differentiation and M-CSF production in mouse band granulocytes in vitro; however, it is not yet known if this molecule can also induce the proliferation and activation of the granulocyte lineage in vivo. In this work we evaluated the induction in vivo of granulopoiesis and the activation of granulocytes in mice treated with CasNa. MATERIAL OR SUBJECTS: BALB/c male mice 8-12 weeks old were used. TREATMENT: The animals were inoculated intraperitoneally with 1 ml of CasNa (10% in PBS p/v) four times (every 48 h). METHODS: Granulocyte proliferation was evaluated by flow cytometry; activation was evaluated by phagocytic indices. The cytokine was measured using an ELISA assay. RESULTS: We show that CasNa increased bone marrow granulopoiesis percentage (38.35 ± 10.88 vs. 64.94 ± 34.14 BrdU+/Gr-1+ cells) and the granulocytes generated presented increased phagocytic indices (0.3 ± 0.1 vs. 0.6 ± 0.11, p < 0.05). We also show that G-CSF (974 ± 411 vs. 3189 ± 350 pg/ml, p < 0.05) and GM-CSF increased in serum, but only G-CSF in bone marrow plasma. CONCLUSIONS: CasNa induces granulopoiesis with functional granulocytes, suggesting that this molecule could be an innate immune system activator.

Antioxidant and Anti-Inflammatory Effect of the Consumption of Powdered Concentrate of Sechium edule var. nigrum spinosum in Mexican Older Adults with Metabolic Syndrome.

Metabolic syndrome (MetS) has a high prevalence in older adults and is a risk factor for cardiovascular diseases and complications of old age. It has also been related to oxidative stress (OxS) and chronic inflammation (CI) and their consequent alterations. Therefore, it is important to propose therapeutic alternatives such as the consumption of Sechium edule (Chayote), since hypoglycemic, hypotensive, and lipogenesis inhibitor properties are attributed to it. We carried out a study in 81 older adults (OA) with MetS to determine the effect of consumption of chayote powder concentrate (500 mg, three times a day) for six months, with a baseline measurement, at three and six months in an experimental group (EG) (n = 41) and a placebo group (PG) (n = 40), all with a diagnosis of MetS according to the criteria of National Adult Treatment Panel of the National Cholesterol Program III (NCEP/ATP III). Anthropometric, biochemical, OxS markers, and inflammation measurements were performed on all participants, basal, three, and six months after. A statistically significant decrease was found in the concentration of lipoperoxides (TBARS), 8-isoprostanes, 8-OHdG, oxidative stress score (OSS), HbA1c, blood pressure, and in the number of MetS diagnostic criteria, as well as an increase in total antioxidant status (TAS), antioxidant gap (GAP), superoxide dismutase (SOD), interleukin 10 (IL-10), and HDL-cholesterol in EG. The results suggest that the consumption of Sechium edule powder has a hypotensive, hypoglycemic, antioxidant, and anti-inflammatory effect in OA with MetS and reduced the percentage of patients with MetS.

Sodium Caseinate in Combination With Daunorubicin or Cytarabine Improves Survival of Mice With Long-established Leukemia.

BACKGROUND/AIM: Although acute myeloid leukemia (AML) has traditionally been considered an oncological emergency and initiation of therapy is believed to be crucial to minimizing disease-related morbidity and mortality, it has also been suggested that a certain delay in treatment has no negative consequences in terms of response, early mortality, or survival. We aimed to determine the effect of administration of sodium caseinate (SC), a salt of casein, the main milk protein, with cytarabine or with daunorubicin on survival in mice with well-established leukemia. MATERIALS AND METHODS: To assay the time of establishment of leukemia in the bone marrow, Balb/c mice were inoculated with 2.5×10 5 WEHI-3 cells/mouse and after 3, 6 and 9 days were euthanized. Bone marrow mononuclear cells (BM-MNCs) of the femur were obtained and cultured for 120 h with or without rmIL-3 and cell proliferation was evaluated by the crystal violet technique. Then, the effect of administrating SC-cytarabine or SC-daunorubicin on survival rates of mice with well-established leukemia was assayed. Another group of Balb/c mice was inoculated with WEHI-3 cell and after 10 days mice were treated with SC-cytarabine or SC-daunorubicin for 40 days. Survival rates were recorded daily and in surviving mice, the prevalence of bone marrow proliferation after treatment was assayed by the crystal violet technique. RESULTS: The assay on the time of establishment of leukemia shows that in 9 days leukemia cells accumulate in the bone marrow in sufficient quantities to sustain an in vitro culture in the absence of growth factors, and we, thus, used this as a criterion of well-established leukemia. When mice with a burden of leukemic cells of more than 9 days were treated with SC-cytarabine or SC-daunorubicin, this resulted in 55% survival for both treatments, and the proliferation assays showed that the bone marrow retained its normal proliferation capacity. CONCLUSION: SC-cytarabine or SC-daunorubicin treatment prolonged the survival rate of Balb/c mice with a burden of well-established leukemia, and there was no negative impact on bone marrow functionality; however, SC-cytarabine or SC-daunorubicin combination options need to be sought to increase survival beyond 40 days.

Pharmacokinetics and Biological Activity of Cucurbitacins.

Cucurbitacins are a class of secondary metabolites initially isolated from the Cucurbitaceae family. They are important for their analgesic, anti-inflammatory, antimicrobial, antiviral, and anticancer biological actions. This review addresses pharmacokinetic parameters recently reported, including absorption, metabolism, distribution, and elimination phases of cucurbitacins. It includes recent studies of the molecular mechanisms of the biological activity of the most studied cucurbitacins and some derivatives, especially their anticancer capacity, to propose the integration of the pharmacokinetic profiles of cucurbitacins and the possibilities of their use. The main botanical genera and species of American origin that have been studied, and others whose chemo taxonomy makes them essential sources for the extraction of these metabolites, are summarized.