Volume 8 Issue 1 (pdf) - Andrew John Publishing Inc

artiCLes infLuenCed BY the WorK of dr. donaLd henderson.
New Insights on Cisplatin Ototoxicity
By Dalian Ding, MS, Jingchun He, Dongzhen yu, Haiyan Jiang, yongqi Li, Richard Salvi, PhD
dding@buffalo.edu
About the Authors
Dalian Ding (left) is with the Center for Hearing and Deafness, University at Buffalo, Buffalo,
NY, USA; the Department of Otorhinolaryngology, Shanghai Sixth Hospital, China; the
Department of Otorhinolaryngology, Third Hospital, Sun Yat-sen University, China; and the
4Department of Otorhinolaryngology, Xiangya Hospital of Central South University, China.
Jingchun He and Dongzhen Yu are with the Department of Otorhinolaryngology, Shanghai Sixth
Hospital, China.
Haiyan Jiang and Richard Salvi are with the Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, USA.
Yongqi Li is with the Department of Otorhinolaryngology, Third Hospital, Sun Yat-sen University, China.
ototoxiCitY
Cisplatin and other platinum-based
compound are widely used to treat a
variety of solid and disseminated forms
of cancer. Although cisplatin and related
platinum compounds are highly effective
anti-tumor agents, their clinical usage is
limited by a number of serious side
effects. Among these side effects,
ototoxicity, neurotoxicity, and nephrotoxicity
are the most common. 1–4 While
ototoxicity is not life threatening, it can
result in severe hearing impairment that
can significantly degrade an individual’s
ability to communicate resulting in social
isolation. Cisplatin ototoxicity can be
particularly devastating when it occurs in
young children because it can impair
language development and social
development.
CisPLatin MeChanisMs
The long-term goal of administering anticancer
drugs such as cisplatin is to block
the uncontrolled proliferation and
growth of cells that from malignant
tumours. When cisplatin enters the
cytoplasm of a cell, chloride ions bound
to cisplatin are displaced by water
molecules; the aquated cisplatin becomes
a potent electrophile that forms intraand
interstrand cross links with DNA
thereby preventing malignant cells from
proliferating further. In addition, cisplatin
binds with intracellular glutathione to
form a toxic cisplatin-glutathione
complex that can kill a malignant or
healthy cell. 5 In order for either of these
reactions to take place, cisplatin must
first be transported from the blood
stream into a malignant or healthy cell.
How does cisplatin enter a cell and where
does it go after it enters
CisPLatin and CoPPer
transPorter
Copper is essential for life; consequently,
cells have developed specialized
transport mechanisms to control its
uptake, export and compartmentalization.
Ctr1, ATP7A, and ATP7B are
three copper transporters that play
prominent roles in regulating
intracellular copper; however they were
also recently shown to regulate the
movement of cisplatin into and out of
cells. Ctr1, located in the cell’s
membrane, is mainly responsible for
transporting copper and cisplatin from
the extracellular environment into the
cytoplasm. 6 ATP7A and ATP7B are
mainly responsible for sequestering
intracellular copper into secretory
vesicles in order to export copper out the
cells. 7 Importantly, Ctr1, ATP7A and
ATP7B were detected by in great
abundance within the organ of Corti,
stria vascularis and spiral ganglion
neurons of the cochlea using immunocytochemistry
4,8 and likely play an
important role in uptake of cisplatin into
the hair cells and spiral ganglion neurons.
CisPLatin dose-resPonse
We used organ cultures of the postnatal
rat cochlea to study cisplatin ototoxicity
in a precise and high controlled. We first
determined the relationship between a
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