Page 12 - Read Online

as well as in vitro. accumulation of doxorubicin and a 4-fold resensitization. [44]

TARGETING CSC SURFACE MARKERS Nanotechnology can be used alone or in combination with
drugs or RNAi of ABC transporters. Triblock copolymers
One potential CSC therapeutics approach is targeting by themselves have been shown to resensitize P-gp-
CSC surface markers. One of the most established and overexpressing tumors to chemotherapeutic drugs; one
commonly used CSC biomarkers is CD44, which is a group incorporated such a copolymer into polylactic acid
cell-surface extracellular matrix receptor. Many studies micelles and reported overcoming multidrug resistance
[6]
represented CD44 antibody therapy as the major anti-CSC (MDR) in a paclitaxel-resistant breast cancer cell line.
[45]
approach. The first of these studies showed that H90 anti- One ABC transporter inhibitor, ritonavir, was conjugated
CD44 therapy successfully eradicated AML. [38] with copolymer nanoparticles to increase uptake into
tumor cells and enhance the cytotoxic effect of doxorubicin
CD133 is a transmembrane glycoprotein and is another in drug resistant murine leukemic cells. Another study
[46]
well-known CSC marker in several tumors such suppressed P-gp using siRNA-loaded dextran polymeric
as glioblastoma, hepatocellular and colon cancers. nanoparticles in conjunction with doxorubicin treatment. [47]
CD133 CSCs have shown resistance to chemotherapy
+
and radiotherapy due to their slower cell cycle, lower ENHANCING IMMUNE RESPONSES
proliferation, higher expression of DNA repair and anti-
apoptotic genes. [39,40] In a study by Carter et al., the It is hypothesized that CSCs are able to evade cancer
[38]
AC133 antibody was conjugated to a potent cytotoxic immunosurveillance due to phenotypic and functional
drug, monomethyl auristatin, using a protease cleavable properties that allow them to survive in immunocompetent
linker. This antibody drug conjugate was efficiently hosts. Antitumor immune cells are detectable and relevant
internalized, co-localized with the lysosome and showed to disease prognosis. Tumor associated antigens (TAA)
high effectiveness against hepatocellular cancer cells. are encoded by lineage specific genes and are often
present or overexpressed on tumor cells. In patients
[48]
EpCAM has been discovered as a CSC marker in solid with metastatic melanoma, circulating CD8 T cells
+
tumors and is correlated with all the characteristics of targeting the TAA MART-1 were detected, although
CSCs. EpCAM /CD44 /CD24 population in breast they were functionally unresponsive. [49,50] These TAA-
-
+
+
cancer had a significantly higher frequency of tumor- specific T cells may be rendered anergic in vivo, and it
initiating cells. Moreover, ovarian cancer cells with high is also plausible that CSCs downregulate their expression
EpCAM expression were involved in EMT, leading to of human leukocyte antigen class 1 molecules or TAAs
metastasis. [2,41] Humanized EpCAM antibodies have been as another means of immunoevasion [49,50] Consequently,
successful in both preclinical and early clinical studies, immunotherapy has become one of the most promising
showing potent anti-tumor activity. [38,41]
treatments for patients with metastatic cancer. Examples
INHIBITING ABC TRANSPORTERS of strategies developed to enhance the host immune
system are nonspecific immunomodulation to activate the
CSC chemoresistance is due in large part to the host’s immune response, and adoptive cell transfer of ex
overexpression of drug efflux pumps such as ABC vivo expanded lymphocytes, such as T cells and natural
transporters. Several pharmacological agents have killer (NK) cells. [48,51]
demonstrated inhibitory or neutralizing effects on these
transporters. There are three generations of inhibitors of Nonspecific immunomodulation includes treatment of
one of the main ABC transporters, P-glycoprotein (P-gp). patients with metastatic cancer using FDA-approved
However, none have been approved for clinical use due cytokines such as IFNα and IL-2. [48,52] Administration
to a lack of specificity and adverse side effects. Recently, of high doses of IL-2 into experimental animals was
a more specific P-gp inhibitor, vardenafil, has shown reported to reduce lung and liver metastases, and further
promise in mitigating the effects of P-gp overexpression. investigation was conducted in human patients with
Vardenafil appeared to directly block P-gp-mediated drug metastatic melanoma, which demonstrated 15-20%
efflux and resulted in increased intracellular concentration objective clinical response. [53,54] Several researches have
and cytotoxicity of paclitaxel and vincristine. [42] attempted to explain the role of IL-2 in immunomodulation,
and proposed that IL-2 induces expansion of T cells
RNAi has also been used to silence ABC transporter with major histocompatibility complex (MHC) -specific
genes. siRNA targeting P-gp reversed drug resistance in recognition of TAA to eliminate target cells. [54,55] One
a doxorubicin-resistant breast cancer model. Doxorubicin- disadvantage of this nonspecific antitumor immune
resistant cell lines are enriched with CSCs upon prolonged activation is it also upregulates the CD4 CD25 Foxp3 +
+
hi
doxorubicin exposure. Exposing the resistant, CSC- regulatory T cell (T ) population, which impedes general
[43]
reg
enriched cells to P-gp siRNA resulted in downregulation antitumor T cell function and contributes to tumor
of P-gp gene expression and led to increased intracellular immunoevasion. [52,56]
236
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ July 8, 2016 ¦