Sesquiterpene lactone potentiates the immunomodulatory, antiparasitic and cardioprotective effects on anti-Trypanosoma cruzi specific chemotherapy

Gonçalves-Santos, Elda; Vilas-Boas, Diego F.; Diniz, Lívia de Figueiredo; Veloso, Márcia Paranho; Mazzeti, Ana Lia; Rodrigues, Maria Rita; Oliveira, Carla Miguel de; Fernandes, Victor Hugo Catricala; Novaes, Rômulo Dias; Chagas‐Paula, Daniela Aparecida; Caldas, Ivo Santana

doi:10.1016/j.intimp.2019.105961

Cited by 23 publications

(7 citation statements)

References 57 publications

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“…Tagitinin C is a sesquiterpene lactone which is widely found in Asteraceae [20]. It has increasingly attracted the interests of researchers because of its various pharmacological activities including antitumor, antiviral, antifibrotic, antiparasitic and cardioprotective effects [21][22][23]. It has been reported that tagitinin C induces the cell death through triggering autophagy in human glioblastoma cells [24]; and in hepatocellular carcinoma (Hep-G2), tagitinin C arrests the cell cycle at sub-G1 and S phase and induces apoptosis [25].…”

Section: Ivyspringmentioning

confidence: 99%

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Wei¹,

Zhao²,

Wang³

et al. 2021

Int. J. Biol. Sci.

177

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Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron-and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion:In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

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Section: Ivyspringmentioning

confidence: 99%

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Wei¹,

Zhao²,

Wang³

et al. 2021

Int. J. Biol. Sci.

177

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“…Accumulating evidence has indicated that combination therapy is a promising approach to achieve a better response in the treatment of T. cruzi experimental infection (5,9,16,(22)(23)(24). In this context, a proof-of-concept evaluation of new benznidazole-sparing regimens in combination with E1224 and in monotherapy is ongoing.…”

Section: Discussionmentioning

confidence: 99%

“…PCRs were performed to amplify T. cruzi DNA using the TaqMan system (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions and using primers for T. cruzi (CzFw 5=-CCACCATTCA TAATTGGAAACAAA-3= and CzRv 5=-CTCGGCTGATCGTTTTCGA-3=) and murine TNF-␣ (TNF-F 5=-GCC CAGACCCTCACACTCA-3= and TNF-R 5=-AACTGCCCTT CCTCCATCTTAAA-3=). It was also used oligonucleotide probes for T. cruzi (5=-FAM-ACCACAACGTGTGATGC-3=-MGB-NFQ) and for TNF-␣ (5=-VIC-TAAGTGTTCCCACACCTC-3=-MGB-NFQ) (23). Amplification cycles were carried out in an ABI 7500 real-time PCR system (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

Machado

Bahia

Caldas

et al. 2020

Antimicrob Agents Chemother

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Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.5) of the combined treatment without additional toxicity to host cells. In vivo experiments, using a murine model of the T. cruzi Y strain in a short-term protocol, demonstrated that amlodipine, although lacking trypanocidal activity, dramatically increased the antiparasitic activity of underdosing ravuconazole regimens. Additional analysis using long-term treatment (20 days) showed that parasitemia relapse until 60 days after treatment was significatively lower in mice treated with the combination (4 out of 14 mice) than ravuconazole monotherapy (10 out of 14 mice), even in the presence of immunosuppressant pressure. Furthermore, the combined therapy was well tolerated and protected the mice from mortality. The treatments also impacted on the cellular and humoral immune response of infected animals, inducing a reduction of serum cytokine levels in all ravuconazole-treated mice. Our findings demonstrate that amlodipine is efficacious in enhancing the antiparasitic activity of ravuconazole in an experimental model of T. cruzi infection and indicates a potential strategy to be explored in Chagas disease treatment.

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“…Moreover, despite its lower in vitro selectivity index, compound 55 was well tolerated during the in vivo assays. Interestingly, it was also found that tagitinin C was able to reduce myocarditis, especially when combined with benznidazole [ 69 ].…”

Section: Terpenic Compounds With Antitrypanosomal Activitymentioning

confidence: 99%

Plant Terpenoids as Hit Compounds against Trypanosomiasis

et al. 2022

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Human African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease) are vector-borne neglected tropical diseases, caused by the protozoan parasites Trypanosoma brucei and Trypanosoma cruzi, respectively. These diseases were circumscribed to South American and African countries in the past. However, human migration, military interventions, and climate changes have had an important effect on their worldwide propagation, particularly Chagas disease. Currently, the treatment of trypanosomiasis is not ideal, becoming a challenge in poor populations with limited resources. Exploring natural products from higher plants remains a valuable approach to find new hits and enlarge the pipeline of new drugs against protozoal human infections. This review covers the recent studies (2016–2021) on plant terpenoids, and their semi-synthetic derivatives, which have shown promising in vitro and in vivo activities against Trypanosoma parasites.

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Sesquiterpene lactone potentiates the immunomodulatory, antiparasitic and cardioprotective effects on anti-Trypanosoma cruzi specific chemotherapy

Cited by 23 publications

References 57 publications

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

Plant Terpenoids as Hit Compounds against Trypanosomiasis

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