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Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010 Page 275

β-catenin independent (non-canonical) pathways. Wnt proteins bind to receptors of the Frizzled and the
low-density lipoprotein receptor-related protein families on the cell surface. Through several cytoplasmic
components, the signal is transmitted to β-catenin which then enters the nucleus and forms a complex with
the transcription factor TCF to activate transcription of Wnt target genes. The activation of the pathway
leads to a variety of biological processes, including cell proliferation, differentiation and migration. Aberrant
oncogenic activation of the Wnt signaling pathway is a common event in different cancer types. Main
mechanisms by which Wnt signaling is dysregulated in cancer are mutations in β-catenin or other key
pathway members, as well as hypermethylation and silencing of gatekeeper antagonists, such as the secreted
frizzled-related protein (SFRP) and dickkopf (DKK), or overexpression of Wnt ligands or receptors, resulting
in increased cancer cell proliferation and migration .
[48]
PI3K/Akt signaling
The activation of PI3K/Akt pathway regulates many different physiological processes, such as transcription,
protein synthesis, metabolic responses and membrane trafficking, and specifically promotes growth and
proliferation of adult stem cells. There are many factors that boost the PI3K/AKT pathway, including
EGF, IGF-1 and insulin. Activation of PI3K phosphorylates and activates AKT, localizing it in the plasma
membrane. AKT has diverse downstream effects, among others activating CREB, inhibiting p27 and
activating mTOR (mammalian target of rapamycin). The pathway is antagonized by PTEN (phosphatase
and tensin homologue). In many cancer types, this pathway is abnormally activated, resulting in reducing
apoptosis and allowing proliferation .
[49]
Notch signaling
Depending on the cellular context, the Notch pathway regulates proliferation, differentiation and apoptosis.
In adult tissues, Notch signaling is involved in tissue homeostasis and stem cell maintenance. The Notch
signaling pathway also plays an established role in embryologic development and its deregulation is associated
with diverse cancer types. It is activated by a receptor-ligand binding between two neighboring cells, leading
to a conformational change of the Notch receptor. Following two cleavages, the Notch intracellular domain
(NICD) is released into the cytoplasm. After translocation into the nucleus, NICD binds to ubiquitous
transcription factor CSL and converts a large co-repressor complex into a transcription activating complex.
The complex activates the transcription of Notch target genes, among others p21, cyclin D1 and 3, c-myc and
members of NF-κB family .
[50]

PLATINUM COMPOUNDS
The origin of platinum-cancer therapy dates back to the year 1965, when it was reported that cisplatin is
an inhibitor of cell division in Escherichia coli . In 1970, it was shown that cisplatin inhibits the growth
[6]
of large tumors, possibly by inhibition of DNA synthesis . Currently, cisplatin is one of the most effective
[7]
chemotherapeutic agents and used for several tumor types. However, its clinical use is limited due to the
severe side effects, including nephrotoxicity and acute kidney injury . Carboplatin has been established as
[51]
the successor to cisplatin with improved tolerability in many therapeutic regimens. This second generation
analogue is closely related to cisplatin. Both cisplatin and carboplatin are the primary first-line therapies
for the treatment of ovarian cancer. They are hydrolyzed in the cell, reacting with the sulfhydryl groups
of proteins and nitrogen atoms of nucleic acids. Their covalent binding with purine bases introduces
DNA damage, such as monoadducts or inter- and intra-strand crosslinks resulting in interference of the
replication machinery, G2/M cell arrest and cell death by apoptosis or necrosis [Figure 1]. They can also
induce oxidative stress by increasing mitochondrial reactive oxygen species and decreasing intracellular
antioxidants, like reduced glutathione (GSH) .
[52]
Characteristics of platinum resistance
Acquired platinum resistance is considered as a multi-factorial process. Numerous mechanisms leading to
the development of drug resistance have been reported and comprehensively considered . They include
[53]