The natural compounds piperovatine and piperlonguminine induce autophagic cell death on Trypanosoma cruzi

Veiga-Santos, Phercyles; Desoti, Vânia Cristina; Miranda, Nathielle; Ueda-Nakamura, Tânia; Dias-Filho, Benedito Prado; Silva, Sueli de Oliveira; Cortez, Diógenes Aparı́cio Garcia; Mello, João Carlos Palazzo de

doi:10.1016/j.actatropica.2012.11.014

Cited by 24 publications

(15 citation statements)

References 29 publications

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“…Traditionally associated to endemic countries, the epidemiology of Chagas disease is changing with an increase of the number of cases in non-endemic countries, mainly, due to human immigration and relocation of the vectors. This underscores the global impact of the disease as well as the urgent need for the development of new anti-trypanosomal agents with lower toxicity and higher activity, particularly for the chronic phase of the disease (Izumi et al 2011;Veiga-Santos et al 2013).…”

Section: Discussionmentioning

confidence: 96%

Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

et al. 2014

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Section: Discussionmentioning

confidence: 96%

Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

et al. 2014

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“…As previously reported, the incubation of bloodstream trypomastigotes with cynaropicrin also induced an intense cytoplasmic vacuolization, with the frequent appearance of multivesicular bodies suggestive of autophagy, a type II programmed cell death (PCD) mechanism. In fact, this type of PCD has already been reported by others during the treatment of T. cruzi with different natural and synthetic trypanocidal compounds, including posaconazole, amiodarone (35), and triazolic naphthofuranquinone (36), among others (37). Interestingly, other types of PCD were also reported when STLs were used against different pathogens.…”

Section: Discussionmentioning

confidence: 96%

Activities of Psilostachyin A and Cynaropicrin against Trypanosoma cruzi In Vitro and In Vivo

Silva

Batista

Araújo

et al. 2013

Antimicrob Agents Chemother

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In vitro and in vivo activities against Trypanosoma cruzi were evaluated for two sesquiterpene lactones: psilostachyin A and cynaropicrin. Cynaropicrin had previously been shown to potently inhibit African trypanosomes in vivo, and psilostachyin A had been reported to show in vivo effects against T. cruzi, albeit in another test design. In vitro data showed that cynaropicrin was more effective than psilostachyin A. Ultrastructural alterations induced by cynaropicrin included shedding events, detachment of large portions of the plasma membrane, and vesicular bodies and large vacuoles containing membranous structures, suggestive of parasite autophagy. Acute toxicity studies showed that one of two mice died at a cynaropicrin dose of 400 mg/kg of body weight given intraperitoneally (i.p.). Although no major plasma biochemical alterations could be detected, histopathology demonstrated that the liver was the most affected organ in cynaropicrin-treated animals. Although cynaropicrin was as effective as benznidazole against trypomastigotes in vitro, the treatment (once or twice a day) of T. cruzi-infected mice (up to 50 mg/kg/day cynaropicrin) did not suppress parasitemia or protect against mortality induced by the Y and Colombiana strains. Psilostachyin A (0.5 to 50 mg/kg/day given once a day) was not effective in the acute model of T. cruzi infection (Y strain), reaching 100% animal mortality. Our data demonstrate that although it is very promising against African trypanosomes, cynaropicrin does not show efficacy compared to benznidazole in acute mouse models of T. cruzi infection.A merican trypanosomiasis, also known as Chagas disease (CD), is a neglected disease caused by the intracellular protozoan Trypanosoma cruzi. Despite a large reduction of new acute cases in recent years due to vectorial transmission control policies, other routes of infection, including vertical transmission (mother to fetus) and ingestion of contaminated food and drinks (1), are still a concern. T. cruzi is restricted to Latin America, where about 10 million people are infected and 25 to 90 million are at risk of acquiring the infection (2). According to the Pan American Health Organization (PAHO) and the World Health Organization (WHO), CD causes between 10,000 and 14,000 deaths per year (3). Currently, only two drugs, benznidazole (Bz) and nifurtimox, are available for chagasic patients (4). However, the poor tolerance to and limited efficacy of these drugs, especially in the later stage of the chronic phase, make the search for novel compounds and therapeutic strategies ever more important as a means to offer alternative therapies to patients refractory to both these nitro derivatives (5).Natural products are an excellent source of active compounds. In fact, despite them comprising Ͻ1 percent of known chemical compounds (DNP 2013 [http://dnp.chemnetbase.com/tour/]; Reaxys 2013 [https://www.reaxys.com/documentation/about _query.htm]), they have supplied or inspired more than half of all new drugs introduced to the market in the last 3 dec...

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“…Because the rate of apoptotic death was not equal to the rate of total cell death induced by PL treatment, other types of cell death must also have occurred in the PL-treated myeloid leukemia cells. Autophagic cell death, another type of programmed cell death, was previously observed in PL-treated cancer cell lines [13] . The upregulated expression of Beclin-1 and LC3B, which are molecular markers PL possesses diverse biological activities, the underlying mechanisms of which remain elusive.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms underlying this phenomenon might involve the preferential binding of PL with ROS-clearance proteins, such as glutathione S-transferase pi 1 (GSTP1) or carbonyl reductase 1 (CBR1), thereby representing a novel cancer therapy strategy of targeting ROS responses. Recently, the anticancer effects of PL have been demonstrated in more cancer cell lines, and multiple mechanisms have been proposed to explain the activity of PL, including the induction of apoptosis [12] , autophagic cell death [13] or cell-cycle arrest [14] . The downstream signaling pathways activated by ROS accumulation in cancer cells include the p38 mitogen-activated protein kinase (p38 MAPK) pathway, the c-Jun N-terminal kinase (JNK) pathway, the extracellular signal-regulated kinase (Erk) pathway and the nuclear factor κB (NFκB) pathway [12,[15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways

Xiong¹,

Liu²,

Qiu

et al. 2015

Acta Pharmacol Sin

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Aim: To investigate the effects of piperlongumine (PL), an anticancer alkaloid from long pepper plants, on the primary myeloid leukemia cells from patients and the mechanisms of action. Methods: Human BM samples were obtained from 9 patients with acute or chronic myeloid leukemias and 2 patients with myelodysplastic syndrome (MDS). Bone marrow mononuclear cells (BMMNCs) were isolated and cultured. Cell viability was determined using MTT assay, and apoptosis was examined with PI staining or flow cytometry. ROS levels in the cells were determined using DCFH-DA staining and flow cytometry. Expression of apoptotic and autophagic signaling proteins was analyzed using Western blotting. Results: PL inhibited the viability of BMMNCs from the patients with myeloid leukemias (with IC 50 less than 20 μmol/L), but not that of BMMNCs from a patient with MDS. Furthermore, PL (10 and 20 μmol/L) induced apoptosis of BMMNCs from the patients with myeloid leukemias in a dose-dependent manner. PL markedly increased ROS levels in BMMNCs from the patients with myeloid leukemias, whereas pretreatment with the antioxidant N-acetyl-L-cysteine abolished PL-induced ROS accumulation and effectively reduced PL-induced cytotoxicity. Moreover, PL markedly increased the expression of the apoptotic proteins (Bax, Bcl-2, and caspase-3) and autophagic proteins (Beclin-1 and LC3B), and phosphorylation of p38 and JNK in BMMNCs from the patients with myeloid leukemias, whereas pretreatment with the specific p38 inhibitor SB203580 or the specific JNK inhibitor SP600125 partially reversed PL-induced ROS production, apoptotic/autophagic signaling activation and cytotoxicity. Conclusion: Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways.

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The natural compounds piperovatine and piperlonguminine induce autophagic cell death on Trypanosoma cruzi

Cited by 24 publications

References 29 publications

Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

Activities of Psilostachyin A and Cynaropicrin against Trypanosoma cruzi In Vitro and In Vivo

Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways

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