Effects of natural products on cisplatin ototoxicity and chemotherapeutic efficacy.

INTRODUCTION: Cisplatin is a very effective chemotherapeutic agent against a variety of solid tumors. Unfortunately, cisplatin causes permanent sensorineural hearing loss in at least two-thirds of patients treated. There are no FDA approved drugs to prevent this serious side effect. AREAS COVERED: This paper reviews various natural products that ameliorate cisplatin ototoxicity. These compounds are strong antioxidants and anti-inflammatory agents. This review includes mostly preclinical studies but also discusses a few small clinical trials with natural products to minimize hearing loss from cisplatin chemotherapy in patients. The interactions of natural products with cisplatin in tumor-bearing animal models are highlighted. A number of natural products did not interfere with cisplatin anti-tumor efficacy and some agents actually potentiated cisplatin anti-tumor activity. EXPERT OPINION: There are a number of natural products or their derivatives that show excellent protection against cisplatin ototoxicity in preclinical studies. There is a need to insure uniform standards for purity of drugs derived from natural sources and to ensure adequate pharmacokinetics and safety of these products. Natural products that protect against cisplatin ototoxicity and augment cisplatin's anti-tumor effects in multiple studies of tumor-bearing animals are most promising for advancement to clinical trials. The most promising natural products include honokiol, sulforaphane, and thymoquinone.

Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity.

Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear cell death through DNA damage, the generation of reactive oxygen species (ROS) and the consequent activation of caspase, glutamate excitotoxicity, inflammation, apoptosis and/or necrosis. Previous studies have demonstrated a role of CXC chemokines in cisplatin ototoxicity. In this study, we investigated the role of CXCL1, a cytokine which increased in the serum and cochlea by 24 h following cisplatin administration. Adult male Wistar rats treated with cisplatin demonstrated significant hearing loss, assessed by auditory brainstem responses (ABRs), hair cell loss and loss of ribbon synapse. Immunohistochemical studies evaluated the levels of CXCL1 along with increased presence of CD68 and CD45-positive immune cells in cochlea. Increases in CXCL1 was time-dependent in the spiral ganglion neurons and organ of Corti and was associated with progressive increases in CD45, CD68 and IBA1-positive immune cells. Trans-tympanic administration of SB225002, a chemical inhibitor of CXCR2 (receptor target for CXCL1) reduced immune cell migration, protected against cisplatin-induced hearing loss and preserved hair cell integrity. We show that SB225002 reduced the expression of CXCL1, NOX3, iNOS, TNF-α, IL-6 and COX-2. Similarly, knockdown of CXCR2 by trans-tympanic administration of CXCR2 siRNA protected against hearing loss and loss of outer hair cells and reduced ribbon synapses. In addition, SB225002 reduced the expression of inflammatory mediators induced by cisplatin. These results implicate the CXCL1 chemokine as an early player in cisplatin ototoxicity, possibly by initiating the immune cascade, and indicate that CXCR2 is a relevant target for treating cisplatin ototoxicity.

Transient Receptor Potential Channels and Auditory Functions.

Significance: Transient receptor potential (TRP) channels are cation-gated channels that serve as detectors of various sensory modalities, such as pain, heat, cold, and taste. These channels are expressed in the inner ear, suggesting that they could also contribute to the perception of sound. This review provides more details on the different types of TRP channels that have been identified in the cochlea to date, focusing on their cochlear distribution, regulation, and potential contributions to auditory functions. Recent Advances: To date, the effect of TRP channels on normal cochlear physiology in mammals is still unclear. These channels contribute, to a limited extent, to normal cochlear physiology such as the hair cell mechanoelectrical transduction channel and strial functions. More detailed information on a number of these channels in the cochlea awaits future studies. Several laboratories focusing on TRPV1 channels have shown that they are responsive to cochlear stressors, such as ototoxic drugs and noise, and regulate cytoprotective and/or cell death pathways. TRPV1 expression in the cochlea is under control of oxidative stress (produced primarily by NOX3 NADPH oxidase) as well as STAT1 and STAT3 transcription factors, which differentially modulate inflammatory and apoptotic signals in the cochlea. Inhibition of oxidative stress or inflammation reduces the expression of TRPV1 channels and protects against cochlear damage and hearing loss. Critical Issues: TRPV1 channels are activated by both capsaicin and cisplatin, which produce differential effects on the inner ear. How these differential actions are produced is yet to be determined. It is clear that TRPV1 is an essential component of cisplatin ototoxicity as knockdown of these channels protects against hearing loss. In contrast, activation of TRPV1 by capsaicin protected against subsequent hearing loss induced by cisplatin. The cellular targets that are influenced by these two drugs to account for their differential profiles need to be fully elucidated. Furthermore, the potential involvement of different TRP channels present in the cochlea in regulating cisplatin ototoxicity needs to be determined. Future Directions: TRPV1 has been shown to mediate the entry of aminoglycosides into the hair cells. Thus, novel otoprotective strategies could involve designing drugs to inhibit entry of aminoglycosides and possibly other ototoxins into cochlear hair cells. TRP channels, including TRPV1, are expressed on circulating and resident immune cells. These receptors modulate immune cell functions. However, whether they are activated by cochlear stressors to initiate cochlear inflammation and ototoxicity needs to be determined. A better understanding of the function and regulation of these TRP channels in the cochlea could enable development of novel treatments for treating hearing loss. Antioxid. Redox Signal. 36, 1158-1170.

Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss.

Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.

Oral Administration of Caffeine Exacerbates Cisplatin-Induced Hearing Loss.

Adenosine A1 receptors (A1AR) are well characterized for their role in cytoprotection. Previous studies have demonstrated the presence of these receptors in the cochlea where their activation were shown to suppress cisplatin-induced inflammatory response and the resulting ototoxicity. Inhibition of A1AR by caffeine, a widely consumed psychoactive substance, could antagonize the endogenous protective role of these receptors in cochlea and potentiate cisplatin-induced hearing loss. This hypothesis was tested in a rat model of cisplatin ototoxicity following oral administration of caffeine. We report here that single-dose administration of caffeine exacerbates cisplatin-induced hearing loss without increasing the damage to outer hair cells (OHCs), but increased synaptopathy and inflammation in the cochlea. These effects of caffeine were mediated by its blockade of A1AR, as co-administration of R-PIA, an A1AR agonist, reversed the detrimental actions of caffeine and cisplatin on hearing loss. Multiple doses of caffeine exacerbated cisplatin ototoxicity which was associated with damage to OHCs and cochlear synaptopathy. These findings highlight a possible drug-drug interaction between caffeine and cisplatin for ototoxicity and suggest that caffeine consumption should be cautioned in cancer patients treated with a chemotherapeutic regimen containing cisplatin.

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea.

Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser727 p-STAT1 and suppressed Tyr705-p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr705-p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.

Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity.

Cisplatin-induced ototoxicity is one of the major factors limiting cisplatin chemotherapy. Ototoxicity results from damage to outer hair cells (OHCs) and other regions of the cochlea. At the cellular level, cisplatin increases reactive oxygen species (ROS) leading to cochlear inflammation and apoptosis. Thus, ideal otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin's chemotherapeutic efficacy. In this study, we show that epigallocatechin-3-gallate (EGCG) is a prototypic agent exhibiting these properties of an effect otoprotective agent. Rats administered oral EGCG demonstrate reduced cisplatin-induced hearing loss, reduced loss of OHCs in the basal region of the cochlea and reduced oxidative stress and apoptotic markers. EGCG also protected against the loss of ribbon synapses associated with inner hair cells and Na+/K+ ATPase α1 in the stria vascularis and spiral ligament. In vitro studies showed that EGCG reduced cisplatin-induced ROS generation and ERK1/2 and signal transducer and activator of transcription-1 (STAT1) activity, but preserved the activity of STAT3 and Bcl-xL. The increase in STAT3/STAT1 ratio appears critical for mediating its otoprotection. EGCG did not alter cisplatin-induced apoptosis of human-derived cancer cells or cisplatin antitumor efficacy in a xenograft tumor model in mice because of its inability to rescue the downregulation of STAT3 in these cells. These data suggest that EGCG is an ideal otoprotective agent for treating cisplatin-induced hearing loss without compromising its antitumor efficacy.

Tonic suppression of PCAT29 by the IL-6 signaling pathway in prostate cancer: Reversal by resveratrol.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. A better understanding of the molecular basis of prostate cancer proliferation and metastasis should enable development of more effective treatments. In this study we focused on the lncRNA, prostate cancer associated transcript 29 (PCAT29), a putative tumor suppressive gene. Our data show that the expression of PCAT29 was reduced in prostate cancer tumors compared to paired perinormal prostate tissues. We also observed substantially lower levels of PCAT29 in DU145 and LNCaP cells compared to normal prostate (RWPE-1) cells. IL-6, a cytokine which is elevated in prostate tumors, reduced the expression of PCAT29 in both DU145 and LNCaP cells by activating signal transducer and activator of transcription 3 (STAT3). One downstream target of STAT3 is microRNA (miR)-21, inhibition of which enhanced basal PCAT29 expression. In addition, we show that resveratrol is a potent stimulator of PCAT29 expression under basal condition and reversed the down regulation of this lncRNA by IL-6. Furthermore, we show that knock down of PCAT29 expression by siRNA in DU145 and LNCaP cells increased cell viability while increasing PCAT29 expression with resveratrol decreased cell viability. Immunohistochemistry studies showed increased levels of STAT3 and IL-6, but low levels of programmed cell death protein 4 (PDCD4), in prostate tumor epithelial cells compared to adjacent perinormal prostate epithelial cells. These data show that the IL-6/STAT3/miR-21 pathway mediates tonic suppression of PCAT29 expression and function. Inhibition of this signaling pathway by resveratrol induces PCAT29 expression and tumor suppressor function.