Targeting thapsigargin towards tumors

Doan, Nhu Thi Quynh; Paulsen, Eleonora S.; Sehgal, Pankaj; Møller, Jesper; Nissen, Poul; Denmeade, Samuel R.; Isaacs, John T.; Dionne, Craig A.; Christensen, Søren Brøgger

doi:10.1016/j.steroids.2014.07.009

Cited by 124 publications

(104 citation statements)

References 32 publications

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“…1987; Doan et al. 2015). Other toxic effects of this plant can include salivary hypersecretion, gastroenteritis, vomiting and diarrhea, nervous disorders, fever, and death in the most severe cases of intoxication (Bnouham et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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“…IP 3 Rs and RyRs are differentially involved in vomiting evoked by different emetogens (Zhong et al, 2014b and 2016). Thapsigargin- and FPL64176-like drugs affecting cytosolic Ca 2+ dynamics are considered as potential targeted apoptotic chemotherapeutics (Cano-Abad et al, 2001; Doan et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT3R and NK1R antagonists.

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“…For example, using the SERCA inhibitor thapsigargin allowed for the sharp accumulation of Ca 2+ in the cytoplasm (due to a spontaneous Ca 2+ leak from the ER) and for the mitochondria to trigger MPT and cell death [26]. Interestingly, a recent study developed a peptide-based modification that targeted thapsigargin (mipsagargin) with high precision to prostate cancer cells and induced selective apoptosis [27]. Similarly, a synthetic steroidal glycoside called SBF-1 was shown to bind to and inhibit SERCA2 activity, thereby causing cancer cell death [28].…”

Section: Introductionmentioning

confidence: 99%