Anti-Cancer and Ototoxicity Characteristics of the Curcuminoids, CLEFMA and EF24, in Combination with Cisplatin

Abstract

In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC50 values: 2–16 μM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75–0.85-fold). Combination treatments reduced A549 migration (0.51–0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin’s effect against A549 migration, but may counteract cisplatin’s effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.

The Mechanism for Anticancer and Apoptosis‐Inducing Properties of Cu(II) Complex with Quercetin and 1,10‐Phenanthroline

“…The reported IC 50 value was 12 μM in A549 cells upon Cu(II) complex exposure [15] . When compared with the literature, IC 50 values for A549 cells were found to be 7.49 and 5.1 at the same treatment period used in this study, [23,24] showing the consistency of our findings. Moreover, the Cu(II) flavonoid complex we used in our study has lower IC 50 values than Cisplatin, which indicates that the complex has the potential to act as an effective metal‐based anticancer drug (Table 1).…”

Synthesis of a novel nitrogen mustard–conjugated bis-terpyridine ruthenium(II) complex as a potent anticancer agent that induces cell cycle arrest and apoptosis

“…For example, complex 4a showed relatively strong antiproliferative activities against the MDA-MB-231, 786-O, A549, and HepG2 cell lines with IC 50 values of 2.6, 3.7, 4.6, and 5.0 μM, respectively, whereas the IC 50 values for 4b were 14.4, 14.1, 7.5, and 24.1 μM. Meanwhile, cisplatin from the literatures 20–23 was used as a competitor, the IC 50 values of which against MDA-MB-231, 786-O, A549, and HepG2 cell lines were 7.8, 10.7, 9.8, and 15.9 μM, respectively, the results are presented in Table 1. Hence, the nitrogen mustard–conjugated terpyridine Ru complex exerted better antiproliferative activities than the corresponding Fe complex 4b and cisplatin.…”

Use of zebrafish larvae lateral line to study protection against cisplatin-induced ototoxicity: A scoping review

“…Several studies have reported that mechanotransducer (MET) channels mediate the entry of cisplatin into cochlear hair cells, but it remains unclear whether MET channels are blocked during that process. 30,46,53 A study using larval zebrafish confirmed that cisplatin-induced damage to the hair cells relies on functional MET channels. 19 Furthermore, the effect of platinum (II) complexes on adult zebrafish auditory system suggested that cisplatin, and to a limited extent phenanthriplatin, can induce hair cells loss in particular regions of the saccule but not the utricle, 56 suggesting either various regional susceptibility to cisplatin or its distinct diffusion or transport pattern.…”

“… 14 , 51 , 52 Cisplatin induces cytotoxicity by binding to the nuclear DNA, leading to apoptosis, particularly in the proliferating cells. 53 In addition to that, cisplatin can mediate the activation of NADPH oxidase 3 (NOX3), which catalyzes the production of superoxide, representing reactive oxygen species (ROS). Overproduction of ROS can activate the signal transducer and activator of transcription 1 (STAT1), inducing the inflammation.…”