co-treated cells under the pH-low condition, indicating that pHLIP-PNA3 specifically resensitised cisplatin-resistant cells in an acidic environment mimicking that of
the tumour microenvironment [53]. In mice, the combined treatment decreased
tumour volume and increased survival and led to reduced blood levels of secreted
IL-6 and reduced tumour expression of IL-6 and ALDH1A1 [53].
4.2 MALAT1
MALAT1 overexpression has been linked with poor prognosis in glioblastoma [62],
a form of childhood neurological cancer that remains notoriously difficult to successfully treat because of the frequent emergence of resistance to front-line treatment
with the chemotherapeutic agent temozolomide (TMZ). This typically manifests as
a multiple drug resistance phenotype in which drug efflux channels and pumps of
the MDR and MRP families are upregulated [63]. There is an urgent need to
find strategies to increase the effectiveness of TMZ treatment and substantially
improve survival outcomes for glioblastoma patients. Recent experimental evidence
indicates that MALAT1 is a key factor in conferring TMZ resistance to glioblastoma
multiforme (GBM) tumours. It is upregulated in TMZ-resistant GBM cell lines that
also exhibit upregulation of multiple drug resistance genes [64]. siRNA knockdown
of MALAT1 resensitised TMZ-resistant GBM cells to TMZ, and gene expression
profiling showed downregulation of all three of the active multiple drug resistanceassociated genes [64].
Another factor involved in the TMZ resistance problem in GBM treatment is the
blood-tumour-brain barrier (BTBB). It has an intrinsically low permeability to free
anticancer compounds in circulation and thus severely hinders their access to
GBM tumours. To overcome this barrier, an immunoliposome-based system
has been developed to deliver drugs across the BTBB to GBM tumours [65].
This comprises a positively charged liposome conjugated with a single-chain variable region fragment of a human anti-transferrin receptor (TfR) monoclonal
antibody (TfRscFv) [66], named scL. It exploits the endogenous activity of TfR in
translocating its ligand, diferric transferrin, across the BBB, and also takes advantage
of the elevated presentation of TfR on the cell surfaces of tumour cells in order to
preferentially deliver the liposome contents across the BTBB and into tumour cells
[66]. Following initial success in using scL to enhance GBM tumour uptake of TMZ
itself [67], the strategy has recently been adapted to usurp TMZ resistance in GBM
by delivering a MALAT1-targeting siRNA to GBM [65]. scL-siMALAT1 treatment
is intrinsically effective at inhibiting GBM cell growth and migration capacity
in vitro and can also suppress glioblastoma stem cell (GSC) stemness [65]. Crucially,
scL-siMALAT1 treatment resensitised TMZ-resistant GSC cells not only to TMZ
but also to cisplatin and irinotecan. Finally, even as a single agent, scL-siMALAT1
inhibited tumour growth in mouse xenograft TMZ-resistant GBM tumours, and
complete remission was achieved in some mice when scL-siMALAT1 was combined with TMZ treatment. Accordingly, overall survival was exclusively increased
among mice administered the combinatorial treatment [65].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
415
the tumour microenvironment [53]. In mice, the combined treatment decreased
tumour volume and increased survival and led to reduced blood levels of secreted
IL-6 and reduced tumour expression of IL-6 and ALDH1A1 [53].
4.2 MALAT1
MALAT1 overexpression has been linked with poor prognosis in glioblastoma [62],
a form of childhood neurological cancer that remains notoriously difficult to successfully treat because of the frequent emergence of resistance to front-line treatment
with the chemotherapeutic agent temozolomide (TMZ). This typically manifests as
a multiple drug resistance phenotype in which drug efflux channels and pumps of
the MDR and MRP families are upregulated [63]. There is an urgent need to
find strategies to increase the effectiveness of TMZ treatment and substantially
improve survival outcomes for glioblastoma patients. Recent experimental evidence
indicates that MALAT1 is a key factor in conferring TMZ resistance to glioblastoma
multiforme (GBM) tumours. It is upregulated in TMZ-resistant GBM cell lines that
also exhibit upregulation of multiple drug resistance genes [64]. siRNA knockdown
of MALAT1 resensitised TMZ-resistant GBM cells to TMZ, and gene expression
profiling showed downregulation of all three of the active multiple drug resistanceassociated genes [64].
Another factor involved in the TMZ resistance problem in GBM treatment is the
blood-tumour-brain barrier (BTBB). It has an intrinsically low permeability to free
anticancer compounds in circulation and thus severely hinders their access to
GBM tumours. To overcome this barrier, an immunoliposome-based system
has been developed to deliver drugs across the BTBB to GBM tumours [65].
This comprises a positively charged liposome conjugated with a single-chain variable region fragment of a human anti-transferrin receptor (TfR) monoclonal
antibody (TfRscFv) [66], named scL. It exploits the endogenous activity of TfR in
translocating its ligand, diferric transferrin, across the BBB, and also takes advantage
of the elevated presentation of TfR on the cell surfaces of tumour cells in order to
preferentially deliver the liposome contents across the BTBB and into tumour cells
[66]. Following initial success in using scL to enhance GBM tumour uptake of TMZ
itself [67], the strategy has recently been adapted to usurp TMZ resistance in GBM
by delivering a MALAT1-targeting siRNA to GBM [65]. scL-siMALAT1 treatment
is intrinsically effective at inhibiting GBM cell growth and migration capacity
in vitro and can also suppress glioblastoma stem cell (GSC) stemness [65]. Crucially,
scL-siMALAT1 treatment resensitised TMZ-resistant GSC cells not only to TMZ
but also to cisplatin and irinotecan. Finally, even as a single agent, scL-siMALAT1
inhibited tumour growth in mouse xenograft TMZ-resistant GBM tumours, and
complete remission was achieved in some mice when scL-siMALAT1 was combined with TMZ treatment. Accordingly, overall survival was exclusively increased
among mice administered the combinatorial treatment [65].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
415