Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

Eryılmaz, Adil; Demirci, Buket; Günel, Ceren; Eliyatkın, Nüket; Aktaş, Safiye; Ömürlü, İmran Kurt; Başal, Yeşim; Sağiroğlu, Mehmet; Ermisler, Baris; Başak, Sema

doi:10.5152/iao.2015.912

Cited by 5 publications

(6 citation statements)

References 15 publications

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“…However, both studies used flawed data to train their model, as their training dataset of non-ototoxic compounds contained drugs for which ototoxicity is reported in the literature. For example, both studies included the chemotherapy agents gallium nitrate and lapatinib in their dataset of ear-safe compounds, despite clinical reports of ototoxicity ( 160 ) or demonstrated hair cell toxicity in animal models ( 161 ). Flawed training datasets will yield less accurate predictions of ototoxicity when applied to new chemical structures.…”

Section: Models For Ototoxicity Studiesmentioning

confidence: 99%

Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

Coffin

Boney²,

Hill

et al. 2021

Front. Neurol.

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Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of in silico screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at in silico, in vitro, and in vivo levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.

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Section: Models For Ototoxicity Studiesmentioning

confidence: 99%

Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

Coffin

Boney²,

Hill

et al. 2021

Front. Neurol.

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“…6-9 Because one of the major issues seen with current forms of breast cancer therapy include the unnecessary death of normal cells of the body-leading to such negative side effects as ototoxicity, cardiotoxicity, infertility, premature menopause, osteoporosis, and other effects-treatment with blackseed oil would seem to be an ideal solution to this issue, where only aggressive cells seem to be negatively affected, while non-aggressive cells are positively affected. 3,4 These results give credence to the notion that the clinical use of blackseed oil for cancer treatment may not only work for targeted killing of aggressive cancerous cells, but also for aiding in the growth of non-aggressive cells in the body. Additionally, the results present a dichotomy between the effects of blackseed oil and TQ on estrogen receptor-positive MCF-7 cells versus estrogen receptor-negative MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 65%

“…These include such effects as ototoxicity, cardiotoxicity, infertility, premature menopause, osteoporosis, and other similarly deleterious ailments. 3,4 As recent studies expound upon the many negative side effects of current drugs used in treating breast cancer, a shift toward more natural remedies for cancer treatment has been seen. One natural remedy that has recently been making a comeback in the field of medicine for treating various cancers is Nigella sativa oil, also known as blackseed or black cumin seed oil.…”

Section: Introductionmentioning

confidence: 99%

Blackseed (Nigella sativa) Oil and its Active Ingredient, Thymoquinone, Suppress the Aggressive Phenotype of Breast Cancer Cells

Chaudhry¹,

Siddiqui²,

Steffen³

et al. 2017

AJUR

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Breast cancer is a leading cause of cancer deaths in women within the United States. However, current treatment methods for the disease present deleterious side effects themselves. Therefore, there is a move towards finding natural cures in order to mitigate negative side effects while still providing effective treatment for the cancer. Blackseed (Nigella sativa) oil is one particular natural remedy, alongside its active ingredient thymoquinone (TQ), which has been successfully tested for suppressing certain types of breast cancer cell proliferation. TQ itself has been seen to be capable of preventing proliferation of both non-aggressive MCF-7 and highly aggressive MDA-MB-231 cancer cells. However, studies which looked at the effects of TQ on MCF-7 cells alone were limiting in their use of high concentrations of the chemical without emphasis on finding a minimum effective dosage. Additionally, a second study which tested the effects of TQ on both MCF-7 and MDA-MB-231 cell lines conducted the experiments in the presence of a lipid-carrier molecule. This, in turn, may have served as a confounding variable in the results. Therefore, it was hypothesized that a minimal effective dosage for both blackseed oil and TQ could be determined, where a significantly greater suppression of MDA-MB-231, in comparison to MCF-7, cell proliferation would be observed. Cell proliferation, cell adhesion, and soft agar assays were used to test the hypothesis of this study. The minimum effective dosage for each substance, characterized by proliferation of the non-aggressive MCF-7 cells to some extent and suppression of the aggressive MDA-MB-231 cells, were determined to be 0.5 µL for blackseed oil and 1.0 µM for TQ. Additionally, TQ’s effectiveness was noted to be more time-dependent than blackseed oil. This study supports the use of minimal effective doses for blackseed oil or TQ to naturally treat breast cancer while preventing damage to non-aggressive cells. KEYWORDS: Breast cancer; Blackseed oil; Nigella sativa; Thymoquinone; Effective dose; Natural remedies

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“…Medications currently implicated in sensorineural hearing loss (SNHL) include salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptics, narcotics, cocaine, antibiotics such as gentamicin and neomycin, and chemotherapeutic agents such as platinum-based agents, monoclonal antibodies, and tyrosine kinase inhibitors. 1-16 Some of these appear to cause damage in a user-dependent, dose-related manner, such as in the case of heroin overdose, polysubstance abuse, and chronic analgesic use. 1-4 Others are medications used at defined doses for targeted antineoplastic therapy, including head and neck, cervical, ovarian, testicular, and breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…1-4 Others are medications used at defined doses for targeted antineoplastic therapy, including head and neck, cervical, ovarian, testicular, and breast cancer. 5-7 The actual mechanisms of SNHL have been a focus of research for decades, and several have been proposed, ranging from cochlear hypoxygenation caused by cocaine-induced vasospasm to apoptosis of outer hair cells (OHCs) caused by cisplatin-generated oxygen free radicals. 7,17 There has also been the proposal of genetic predisposition to drug-induced SNHL, which could explain why the above agents, when given in similar doses, cause some to experience hearing loss, whereas others do not.…”

Section: Introductionmentioning

confidence: 99%