Substance P receptor blocker, aprepitant, inhibited cutaneous and other neurogenic inflammation side effects of the EGFR1-TKI, erlotinib

Chmielinska, Joanna J.; Kramer, Jay H.; Mak, I. Tong; Spurney, Christopher F.; Weglicki, William B.

doi:10.1007/s11010-019-03677-7

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…Aprepitant also showed antioxidant activity in glioblastoma-derived cell lines by reducing the expression of thioredoxin reductase [ 39 ]. It has also been reported that this NK1R antagonist suppresses superoxide activity in glioblastoma-induced rats by inhibiting neutrophil activity [ 40 ]. To the best of our knowledge, this was the first time that the antioxidant activity of the lower concentrations of this agent (20 μ M) has been tied with its anticancer effects, and our study suggested that aprepitant probably reduced the survival of glioblastoma cells via blocking the oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification

Rezaei

Darban

Javid

et al. 2022

BioMed Research International

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Although there is no doubt regarding the involvement of oxidative stress in the development of glioblastoma, many questions remained unanswered about signaling cascades that regulate the redox status. Given the importance of the substance P (SP)/neurokinin 1 receptor (NK1R) system in different cancers, it was of particular interest to evaluate whether the stimulation of this cascade in glioblastoma-derived U87 cells is associated with the induction of oxidative stress. Our results showed that SP-mediated activation of NK1R not only increased the intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS) but also reduced the concentration of thiol in U87 cells. We also found that upon SP addition, there was a significant reduction in the cells’ total antioxidant capacity (TAC), revealing that the SP/NK1R axis may be involved in the regulation of oxidative stress in glioblastoma cells. The significant role of SP/NK1R in triggering oxidative stress in glioblastoma has become more evident when we found that the abrogation of the axis using aprepitant reduced cell survival, probably through exerting antioxidant effects. The results showed that both MDA and ROS concentrations were significantly reduced in the presence of aprepitant, and the number of antioxidant components of the redox system increased. Overall, these findings suggest that aprepitant might exert its anticancer effect on U87 cells through shifting the balance of oxidant and antioxidant components of the redox system.

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Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification

Rezaei

Darban

Javid

et al. 2022

BioMed Research International

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“…Doxorubicin cardiotoxicity is mediated by the SP/NK-1R system, and it is known that aprepitant decreases cardiotoxicity and increases the sensitivity of tumor cells to doxorubicin (Table 2) [98]. Moreover, in preclinical studies, it has been demonstrated that aprepitant exerts a protective role against the hepatotoxicity and nephrotoxicity induced by the chemotherapeutic drug cisplatin [108] and that aprepitant (2 mg/kg/day for 12 weeks) inhibited the cutaneous (e.g., nose crusting, scabbing, skin reddening and alopecia) and neurogenic inflammation side-effects mediated by erlotinib (an epidermal growth factor receptor-tyrosine kinase inhibitor used as an anticancer treatment) [109]. Erlotinib increases the level of SP, which mediates the side-effects observed, whereas aprepitant mitigates it, including causing a decrease in the number of NK-1Rs expressed in the skin.…”

Section: Relationships Between Aprepitant and Other Drugsmentioning

confidence: 99%

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

Muñoz

Coveñas

2020

Cancers

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Neurokinin-1 receptor (NK-1R) antagonists exert antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exert multiple actions against cancer: antiproliferative and anti-Warburg effects and apoptotic, anti-angiogenic and antimetastatic effects. These multiple effects have been shown for a broad spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as an antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed, as is the possible link, through the substance P (SP)/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant, and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

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“…Erlotinib has been FDA approved for over a decade in NSCLC and is produced by Genentech. Most common AEs related to Erlotinib included cutaneous changes such as rash and hair loss, as well as other neurogenic inflammation [208].…”

Section: Erlotinib (Tarceva; Genentech)mentioning

confidence: 99%

Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?

Beinhoff

Sabharwal

Udhane

et al. 2021

Cancers

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Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

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Substance P receptor blocker, aprepitant, inhibited cutaneous and other neurogenic inflammation side effects of the EGFR1-TKI, erlotinib

Cited by 16 publications

References 30 publications

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?

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