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Targeting Cancer Stem Cells by Curcumin and Clinical Applications

1. Curcumin, derived from turmeric, has shown potential to target cancer stem cells through regulating pathways involved in stem cell self-renewal like Wnt/b-catenin and specific microRNAs related to epithelial-mesenchymal transition. 2. Studies demonstrate curcumin can reduce the formation of tumorspheres in breast cancer cells, suggesting it preferentially targets breast stem cells over differentiated cells. 3. While curcumin and its analogs show promise in inhibiting cancer stem cells in various cancer types based on cell and animal studies, improved formulations are needed to enhance its bioavailability for clinical applications in humans.

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Muhammad Harmen Reza Siregar
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67 views3 pages

Targeting Cancer Stem Cells by Curcumin and Clinical Applications

1. Curcumin, derived from turmeric, has shown potential to target cancer stem cells through regulating pathways involved in stem cell self-renewal like Wnt/b-catenin and specific microRNAs related to epithelial-mesenchymal transition. 2. Studies demonstrate curcumin can reduce the formation of tumorspheres in breast cancer cells, suggesting it preferentially targets breast stem cells over differentiated cells. 3. While curcumin and its analogs show promise in inhibiting cancer stem cells in various cancer types based on cell and animal studies, improved formulations are needed to enhance its bioavailability for clinical applications in humans.

Uploaded by

Muhammad Harmen Reza Siregar
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Targeting cancer stem cells by curcumin and clinical applications

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an


Indian spice.

The anticancer effect of curcumin has been demonstrated in many cell and animal studies,
and recent research has shown that curcumin can target cancer stem cells (CSCs).

CSCs are proposed to be respon- and maintaining cancer, and contribute to recurrence and
drug resistance.

A number of studies have suggested that curcumin has the potential to target CSCs through
regulation of CSC self-renewal pathways (Wnt/b-catenin, Notch, sonic hedgehog) and
specific microRNAs involved in acquisition of epithelial–mesenchymal transition (EMT).

The potential impact of curcumin, alone or in combination with other anticancer agents, on
CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been
well-established by numerous clinical studies.

Importantly, the low bioavailability of curcumin has been dramatically improved through the
use of structural analogues or special formulations.

More clinical trials are underway to investigate the efficacy of this promising agentnin cancer
chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-
renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human
studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer
treatments.

Introduction

1. Curcumin is a well-known dietary polyphenol derived from therhizomes of turmeric


(Curcuma longa), an Indian spice, which is usually used in preparation of mustard and
curryThree curc-uminoids, namely curcumin, demethoxycurcumin, and bisdeme-
thoxycurcumin, are present in the natural extracts of C.
2. Curcumin is well known to possess anti-inflammatory, antioxi-dant, and antimicrobial
activities, and has also been inten-sively studied as a cancer chemopreventive agent in
a wide range of cancer models, including melanoma, head and neck, breast, co- lon,
pancreatic, prostate, and ovarian cancers, over the past three decades. A plethora of
molecular targets and signaling path- ways, such as NF-j B, Akt/mTOR, and HIF-1,
have been shown to be modulated by curcumin, resulting in inhibition.
3. Curcumin regulates many molecular targets involved in cancer development, as
revealed by extensive cell and animal studies.
4. Several studies have demonstrated that curcumin affects multi- ple components of
Wnt/b-catenin signaling directly or indirectly in breast, gastric, colon, intestinal,
osteosarcoma, and medulloblas- toma cancer cells.
5. The microRNAs (miRNAs), short non-coding RNAs (20–24 nucleotides), regulate
approximately one-third of protein-coding genes at post-transcriptional level by
specifically binding to target mRNAs and leading to their degradation or inhibition of
translation. While cancer cells have been demonstrated to have abnormal miRNA
profiles, a number of studies have supported the role of specific miRNAs in CSC
phenotype including self-renew.
6. Lim et al. performed microarray analysis and revealed a signif- icant down-regulation
of Gli1 expression after ‘‘nanocurcumin’’ (a polymeric nanoparticle formulation of
curcumin) treatment in
brain tumor cells, which was further supported by the results of quantitative real-time
PCR. Curcumin was reported to act sim-ilarly to the hedgehog antagonist
cyclopamine, lowering Gli mRNA level as well as Gli reporter activity in prostate
cancer cells The protein levels of SHH, Gli1, and Ptch1 all declined after curcu- min
treatment, triggering apoptosis of medulloblastoma cells.
7. Epithelial–mesenchymal transition (EMT) is the transition from epithelial cells to
mesenchymal cells which are closely related to CSCs. Mesenchymal stem cells can
re-program to CSCs due to change in microenvironment. The connection between
miRNAs and the acquisition of EMT has been explored. For exam- ple, drug-resistant
cancer cells were low in miR-200 level and exhibited more EMT properties. Several
studies highlighted that miR-200 suppressed CSC formation, which was associated
with decreased expression of Notch-1 and a few other regulators of CSCs and EMT.
Shimono et al. found varying levels of 37 miRNAs in human breast CSCs and non-
CSC cancer cells,and reported that miR-200c strongly suppressed tumor formation
driven by human breast CSCs in vivo.
8. During the past few years, a number of studies have investi- gated the potential
impact of curcumin (alone or in combination with other anticancer agents) on CSCs in
vitro by utilizing tumor- sphere formation, side population, enzyme activity, and cell-
sur- face marker assays, as well as in vivo in animal models.
9. One of the unique properties of CSCs is to survive in serum-free, non-adherent
suspensions to produce tumorspheres or spheres. Curcumin (5lM) reduced
mammosphere formation by 50%, while 10l M curcumin completely eliminated
mammosphere formation. Of special note, the total cell viability was as high as 89%
at 5l M curcumin, suggesting a preferential target of breast stem cells compared to
differentiated cells. Furthermore, the inhibitory effect of curcumin on the self-renewal
capacity
was demonstrated by the declined number of secondary spheres and a complete
absence of tertiary spheres upon serial passage.

Conclusion and future perspectives

Curcumin, as well as its modified forms (analogues or nanopar-ticle-encapsulated


formulations), has shown great potential to inhibit CSCs in several types of cancer both in
cell cultures and in mouse models, including glioma, breast, colorectal, pancreatic, brain, and
esophageal cancers.

Some analogues (e.g., CDF) and formulations (e.g., nanotechnology-based formulation) have
exhibited improved efficacy against CSC-like cells and greater growth-inhibitory capacity in
tumors. It is promising to evaluate curcumin and its modified forms in other types of CSCs.

Further- more, a number of studies have shown that regula tion of Wnt/b-catenin, SHH,
Notch, EMT, and specific microRNAs involved in acquisition of EMT and CSC self-renewal
may contribute to these protective effects; however, the underlying molecular mechanisms
remain unclear.
Elucidation of the mechanisms and the connec- tions between these signaling pathways is
warranted in the future.

Curcumin, as a natural remedy for thousands of years, has been shown to be well tolerated
and causes no significant toxicity in a number of clinical trials.

The major drawback of curcumin as a chemopreventive or therapeutic agent is its low


bioavailability, which has been dramatically improved through the use of structural ana-
logues or special formulations.

For instance, structural analogues,nanoparticles, lipoid particles, and lecithin formulation


have been tested in human participants.

More human studies are necessary to assess these modified forms of curcumin, in regards to
both safety and efficacy.

In conclusion, curcumin especially its novel analogues and for- mulations could be a very
promising adjunct to traditional cancer treatments including chemotherapy and radiotherapy,
especially given the fact that most chemotherapeutic drugs and radiotherapy do not have the
capability to eliminate CSCs and therefore are often fol lowed by tumor resistance and
recurrence.

This combination strategy will open a new avenue for more effective therapies for cancer
patients.

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