Combination therapy with TiO2 nanoparticles and cisplatin enhances chemotherapy response in murine melanoma models

Background Despite recent progressions in the treatment of melanoma, the response to conventional therapies and the long-term survival in melanoma patients still remain poor. Recently, the use of nanoparticles (NPs) has been highlighted for promoting the chemotherapeutic effects of cytotoxic drugs in melanoma. The aim of this study is to mechanistically evaluate the potential of titanium dioxide (TiO2) nanoparticles (NPs) for enhancing chemotherapy effects in in vitro and in vivo models of murine melanoma. Methods The F10 melanoma cells were exposed to different concentrations of TiO2 NPs and/or cisplatin, then cell growth, cell viability, and cell death were evaluated. In parallel, C57BL/6 syngeneic melanoma mice were treated by TiO2 NPs and/or cisplatin, and then drug responses, tumor size and mice’s organs were studied pathologically. Autophagy was examined by evaluating the formation of autophagosomes and gene expression levels of autophagy markers (ATG5 and ATG6) by fluorescent microscopy and qPCR, respectively. Results Nontoxic concentrations of TiO2 NPs (50 µg/ml) promote anti-proliferative and cytotoxic effects of cisplatin in F10 melanoma cells, which is mediated through the induction of autophagy and necrotic cell death. Whereas TiO2 NPs have no cytotoxic or metastatic effects in melanoma mice, its combination with cisplatin enhances drug responses (up to 50%), leading to higher inhibition of tumor growth compared with each monotherapy. Conclusion The combination of TiO2 NP with cisplatin enhances chemotherapy response in both in vitro and in vivo melanoma models. In addition, autophagy plays an essential role during sensitizing melanoma cells to chemotherapy (AU)

Combination therapy with TiO2 nanoparticles and cisplatin enhances chemotherapy response in murine melanoma models.

BACKGROUND: Despite recent progressions in the treatment of melanoma, the response to conventional therapies and the long-term survival in melanoma patients still remain poor. Recently, the use of nanoparticles (NPs) has been highlighted for promoting the chemotherapeutic effects of cytotoxic drugs in melanoma. The aim of this study is to mechanistically evaluate the potential of titanium dioxide (TiO2) nanoparticles (NPs) for enhancing chemotherapy effects in in vitro and in vivo models of murine melanoma. METHODS: The F10 melanoma cells were exposed to different concentrations of TiO2 NPs and/or cisplatin, then cell growth, cell viability, and cell death were evaluated. In parallel, C57BL/6 syngeneic melanoma mice were treated by TiO2 NPs and/or cisplatin, and then drug responses, tumor size and mice's organs were studied pathologically. Autophagy was examined by evaluating the formation of autophagosomes and gene expression levels of autophagy markers (ATG5 and ATG6) by fluorescent microscopy and qPCR, respectively. RESULTS: Nontoxic concentrations of TiO2 NPs (50 µg/ml) promote anti-proliferative and cytotoxic effects of cisplatin in F10 melanoma cells, which is mediated through the induction of autophagy and necrotic cell death. Whereas TiO2 NPs have no cytotoxic or metastatic effects in melanoma mice, its combination with cisplatin enhances drug responses (up to 50%), leading to higher inhibition of tumor growth compared with each monotherapy. CONCLUSION: The combination of TiO2 NP with cisplatin enhances chemotherapy response in both in vitro and in vivo melanoma models. In addition, autophagy plays an essential role during sensitizing melanoma cells to chemotherapy.

Temporary and permanent level shifts in distortion product otoacoustic emissions following noise exposure in an animal model.

BACKGROUND: Noise-induced hearing loss (NIHL) is one of the most common occupational illnesses. Most of the studies on NIHL were conducted at high noise levels that people are rarely exposed to but in industries. The function of the outer hair cells (OHCs) is impaired after exposure to industrial noise. Distortion product otoacoustic emissions (DPOAEs) are useful in examination of noise-induced level shifts. OBJECTIVE: To assess the function of OHCs by DPOAE temporary and permanent level shifts (TLSdp and PLSdp) in rabbits exposed to white noise at realistic levels typically found in industrial settings over a broad range of frequencies. METHODS: 12 albino rabbits were divided into two groups: the experimental group rabbits which were exposed to 95 dB SPL white noise at 500-8000 Hz for 8 hrs/day for 5 consecutive days, and the control group rabbits with no exposure to noise. The function of OHCs was examined by DPOAE level (Ldp) in different occasions. The study groups were compared for DPOAE temporary and permanent level shifts (TLSdp and PLSdp) to assess the effect of noise on OHCs function. RESULTS: Noise-induced DPOAE levels (Ldp) were decreased up to 20.65 dB (on day 8) and 18.93 dB (on day 11) at 5888.50 Hz (p = 0.081). TLSdp and PLSdp were significantly decreased up to 17.99 dB and 16.27 dB, respectively in the experimental group. The most and least Ldp were significantly different (p<0.05); they occurred at 5888.50 and 588.00 Hz, respectively. There were significant differences between temporary and permanent threshold shift at various frequencies (p<0.05). These differences were mainly related to 5888.50 Hz compared to other frequencies in each ear (p<0.05). CONCLUSION: DPOAEs are an attractive tool for obtaining information about small temporary or permanent threshold shifts, even when the pure tone audiogram is normal.

Noise-induced Outer Hair Cells' Dysfunction and Cochlear Damage in Rabbits.

BACKGROUND: Outer hair cells' (OHCs') dysfunctions as the extent of temporary and permanent threshold shifts (TTS and PTS) and cochlear damage were assessed in rabbits exposed to continuous noise METHODS: Twelve New Zealand white rabbits were studied in noise (N) (n=6; exposed to continuous noise; 95 dB SPL, 500-8000 Hz for 8 h per day during 5 consecutive days) and control (C) (n=6; not exposed to noise). OHCs' functions were assessed by distortion product otoacoustic emission (DPOAE) level (Ldp) measurements in different periods and comparing TTS and PTS. Animals were anaesthetized by CO2; cochleae were extracted, fixed in 10% formaldehyde for 48 hours, decalcified by 10% nitric acid for 24 hours, and dehydrated, embedded, sectioned 5 µm thickness and stained by Hematoxylin and Eosin for light microscopy. RESULTS: The most and least Ldp or TTS or PTS were related to 5888.50 Hz and 588.00 Hz respectively in noise subjected rabbits (P<0.05). TTS and PTS were decreased up to 17.79 dB and to 16.01 dB respectively. TTS were more than PTS over all test frequencies, especially at 5888.50 Hz (P<0.05). Ldp or TTS or PTS were found to be equal across ears (P>0.05). Severely vacuolated OHCs, pyknotic IHCs, swollen SC, and slightly thickened BM were found. CONCLUSION: Continuous noise extensively led to OHCs' dysfunctions as decreased Ldp (both TTS and PTS) and highly damage to cochlea.