Review

Doxorubicin, mesenchymal stem cell toxicity and

antitumour activity: implications for clinical use
Mia Baxter-Hollanda and Crispin R. Dassa,b
a
School of Pharmacy and Biomedical Science, Curtin University, and bCurtin Health Innovation Research Institute, Perth, WA, Australia

Keywords
cancer; chemotherapy; doxorubicin; stem
cell; toxicity
Correspondence
Crispin R. Dass, School of Pharmacy and
Biomedical Science, Curtin University, GPO
Box U1987, Perth, WA 6845, Australia.
E-mail: Crispin.Dass@curtin.edu.au
Received July 19, 2017
Accepted November 25, 2017
doi: 10.1111/jphp.12869
Abstract
Objectives The use of doxorubicin, an antineoplastic medication used for the
treatment of cancers via mechanisms that prevent replication of cells or lead to
their death, can result in damage to healthy cells as well as malignant. Among the
affected cells are mesenchymal stem cells (MSCs), which are involved in the
maintenance and repair of tissues in the body. This review explores the mecha-
nisms of biological effects and damage attributed to doxorubicin on MSCs. The
PubMed database was used as a source of literature for this review.
Key findings Doxorubicin has the potential to lead to significant and irreversible
damage to the human bone marrow environment, including MSCs. The primary
known mechanism of these changes is through free radical damage and activation
of apoptotic pathways. The presence of MSCs in culture or in vivo appears to
either suppress or promote tumour growth. Interactions between doxorubicin
and MSCs have the potential to increase chemotherapy resistance.
Summary Doxorubicin-induced damage to MSCs is of concern clinically. How-
ever, MSCs also have been associated with resistance of tumour cells to drugs
including doxorubicin. Further studies, particularly in vivo, are needed to provide
consistent results of how the doxorubicin-induced changes to MSCs affect treat-
ment and patient health.

Introduction Class of drug, chemical structure and

mechanism of action
Doxorubicin is a medication employed in treatment regi-
mens of the ever-growing epidemic of cancer. Antineo- Doxorubicin (also known by trade names of Adriamycinâ,
plastic drugs used for chemotherapy are renowned for Doxilâ, Myocetâ) is classed as an anthracycline antibiotic anti-
their extensive side-effect profile, which ranges from neoplastic drug, derived from the Streptomyces peucetius var.
unpleasant to fatal, and doxorubicin is no exception.
Doxorubicin’s mechanism of action involves inhibition of
the synthesis of and damage to DNA, and formation of
reactive oxygen species (ROS) to create oxidative stress in
the cellular environment. These effects are not limited to
tumour cells; healthy cells are also affected, including
stem cells. As they are responsible for the growth and
repair of a wide range of tissues in the body, damage to
stem cells has the potential to cause lifelong health prob-
lems for a patient treated with doxorubicin. This review
discusses the potential ways doxorubicin can influence
cells, the current observed effects of chemotherapy on
stem cells, particularly mesenchymal stem cells (MSCs),
and what is already known about doxorubicin’s effects on
stem cells, but which has not been reviewed in this man-
ner to date.

320 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 320–327
Mia Baxter-Holland and Crispin R. Dass
Caesius bacteria.[1] The anthracycline backbone is com-
prised of a tetracyclic aglycone ring with adjacent quinone-
hydroquinone groups and an attached daunosamine
sugar.[1,2] Doxorubicin is distinguished from other anthra-
cyclines by the addition of a methoxy group to the tetra-
cyclic ring system, and methyl groups to the C-9 side chain
and daunosamine sugar.[2]
Anthracyclines, including doxorubicin, exert their action
via multiple mechanisms. These biological effects do not
discriminate between cells of cancers and healthy cells and
are discussed in turn below.
Inhibition of DNA synthesis
It has been shown that doxorubicin is able to intercalate
deoxyribonucleic acid (DNA) via the insertion of doxoru-
bicin as a planar chromophore between the planar DNA
base pairs, binding to them via hydrogen bonds.[3] The
drug’s hydroxyl and sugar amino groups are responsible for
these covalent interactions.[4,5] Intercalation of DNA results
in double-stranded DNA breakage and gives rise to apopto-
sis.[3,4] Doxorubicin has also been shown to lead to the
inhibition of DNA and RNA polymerase enzymes, though
it was found to have a higher preference for DNA poly-
merase.[6] Blockage of these enzymes prevents a cell from
undergoing normal DNA and RNA synthesis.[3,6] It must
be noted that outcomes of in-vivo studies on doxorubicin’s
DNA and RNA polymerase inhibition are inconclusive –
some show that plasma concentrations above those used
therapeutically (approximately 1–2 lM) are required for
such effects, while others display enzyme inhibition at these
levels. It has been proposed that enzyme inhibition is only a
cytostatic (rather than cytotoxic) and transient component
of drug action.[3]
Interference of topoisomerase II activity
Topoisomerase II is an enzyme that regulates DNA topol-
ogy (the pattern by which two complementary strands are
intertwined) via creating temporary cuts in both strands
of DNA during replication. This relaxes the DNA and pre-
vents both negative and positive superhelical twists, knots
and nucleic acid tangles.[7,8] Doxorubicin takes advantage
of topoisomerase II by stabilising the enzyme-DNA inter-
mediate complex that is responsible for the cleavage,
resulting in higher concentrations of the complex within
the cell. Thus, more than the standard number of double-
stranded DNA cuts are formed and rather than being tran-
sient, much of the damage becomes permanent.[8] Cell
death then occurs as fragmented DNA cannot be tran-
scribed, and the cell is unable to undergo normal mitotic
processes.
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 320–327
Doxorubicin and stem cells
Free radical damage to cells
Doxorubicin is able to accept an electron at its quinone
groups, forming a semiquinone in the presence of enzymes
NADH dehydrogenase, xanthine oxidase and cytochrome
P450 reductase. This semiquinone can damage DNA itself
as well as return to its parent quinone by reducing oxygen,
forming ROS such as hydrogen peroxide and superox-
ide.[3,9,10] Under normal conditions tissues can tolerate the
presence of ROS. However, when levels exceed the capacity
of intrinsic antioxidant defences, cellular damage occurs.
This includes DNA strand scission and peroxidation of
unsaturated fatty acids leading to cellular membrane
damage.[3,10]
Doxorubicin is given via intravenous injection or infu-
sion and typically displays a triphasic plasma clearance and
a terminal half-life of 24–36 h.[11] Doxorubicin is used in
multidrug regimens in the treatment of cancers including
but not limited to solid tumours such as breast cancer,[1]
ovarian cancer[12] and osteosarcoma[3] as well as
haematopoietic malignancies such as lymphomas and leu-
kaemia.[13]
Stem cells: an overview
Stem cells can be subdivided into two main groups: adult/
somatic and embryonic stem cells.[14] Embryonic stem cells
(ESCs) are derived from the inner cell mass of a human
blastocyst, which forms 3 to 5 days after an egg is fertilised.
These cells are described as pluripotent because there is a
possibility for them to develop into all three embryonic
germ layers: endoderm (gut epithelium); ectoderm (neutral
epithelium, embryonic ganglia and stratified squamous
epithelium); and mesoderm (cartilage, bone, smooth
muscle and striated muscle).[15] ESCs are shown to express
high levels of telomerase, a ribonucleoprotein that is
involved in maintaining telomere length. The expression of
this protein is correlated with immortality in cell lines,
allowing ESCs to have a long replicative lifespan and main-
tain the capacity to differentiate into the three germ layers
in vitro.[15]
Somatic stem cells are present in almost every tissue in
an adult body and have a narrower differentiation potential
than ESC, only being able to differentiate into several or a
single type of cell. They are used for tissue maintenance
and repair.[14] The bone marrow is a large source of
somatic stem cells, including both subcategories:
haematopoietic and mesenchymal.[14] MSCs are able to dif-
ferentiate into osteoblasts (bone), adipocytes (fat), chon-
drocytes (cartilage) and myoblasts (muscle);[14]
haematopoietic stem cells can form every type of blood cell,
such as erythrocytes and platelets.[16]
321
Doxorubicin and stem cells
Mesenchymal stem cells
When isolated, MSCs are normally derived from bone mar-
row, however are also present in umbilical cord blood, sali-
vary glands, adipose tissue and other organs including the
gut.[17,18] The International Society for Cellular Therapy
states that in order for a cell to be classed as MSC, it must
(1) possess certain surface markers such as CD105, CD70
and CD90 and lack expression of others including CD45,
CD34, CD14 or CD11b, (2) must be plastic-adherent when
maintained in standard culture conditions and (3) must
differentiate to osteoblasts, adipocytes and chondroblasts
in vitro.[19] The differentiation of MSCs firstly involves
commitment to a lineage-specific progenitor and then mat-
uration from progenitors to a specific cell type.[20] Lineage
commitment is under the control of several critical sig-
nalling pathways, including wingless-type MMTV integra-
tion site (Wnt), Hedgehog, Notch, transforming growth
factorb (TGFb) and bone morphogenetic protein (BMP),
and fibroblast growth factors. It has also been proposed
that the nature of the cell’s microenvironment has some
control over its fate, with the phenotype formed being
determined by the level of surrounding tissue elasticity. For
example, MSCs in rigid matrices that resemble bone give
rise to osteogenic progenitors; softer matrices mimicking
brain give neurogenic cells.[21] More recently, differentia-
tion has been found to be under the influence of micro-
RNAs, molecules that control post-translational gene
expression.[20,22] By targeting transcription factors, micro-
RNAs can up- or downregulate the differentiation of differ-
ent cell lineages.[22]
Patterns of differentiation
In-vitro studies have proposed a hierarchal model of differ-
entiation, with the early MSCs undergoing a sequential loss
of lineage potential as they differentiate down the proposed
levels; first adipogenic is lost, then chondrogenic. Following
this, the residual cells were found to be primarily osteo-
genic, suggesting that the osteogenic pathway is the ‘de-
fault’ outcome remaining if a cell is not committed to
another phenotype.[23,24] Formation of mature osteocytes is
a multistep process. Firstly, the cells differentiate into pre-
osteoblasts under the direction of multiple signalling path-
ways and transcription factors such as RUNX2.[25] Sec-
ondly, TGFb induces the migration of pre-osteoblasts to
sites of bone resorption,[26] the microenvironment of which
is stiff and elastic (thus favouring osteogenesis) and where
mechanical factors promote a more flattened cell
shape.[21,27] Then, local soluble factors including BMP and
insulin-like growth factors (IGFs) activate multiple sig-
nalling pathways which promote pre-osteoblast maturation
into mineralised tissue.[28]
322 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 320–327
Mia Baxter-Holland and Crispin R. Dass
Effects of chemotherapeutics on
stem cells
Medication-induced elevation of ROS is one method of tar-
geting cancer cells via causing damage to proteins, DNA
and lipids.[29] Stem cells have mechanisms for DNA repair
and oxidative stress defence. Compared to somatic cells,
ESCs have been shown to have higher antioxidant enzyme
levels, including superoxide dismutase and glutathione/
thioredoxin systems, and reduced accumulation of ROS,
resulting in a better defence mechanism against oxidative
stress.[30] However, these features were lost upon differenti-
ation. In-vitro studies[29,31] found that higher levels of ROS
were associated with suppression of MSC osteogenesis
while favouring adipogenesis. Free radical generation adja-
cent to rodent bones in vivo is associated with formation of
new osteoclasts and higher levels of bone resorption, not
unlike the effects of signalling molecules such as parathy-
roid hormone (PTH) and interleukin-1 (IL-1).[32] PTH
and IL-1 induce osteoclastic breakdown of bone to release
minerals with the intention of raising the levels of free cal-
cium, phosphate, magnesium and other minerals in the
blood: tipping the balance in favour of resorption over ossi-
fication. Indeed, higher levels of oxidative stress have been
associated with reduced bone mineral density and higher
risks of osteoporosis.[33]
Nicolay et al. studied the effects of bleomycin, an anti-
neoplastic drug which forms free radicals and induces
double-stranded DNA breaks, on MSCs.[34] It was found
that following the administration of the drug, MCSs
underwent an increased rate of apoptosis and while their
adipogenic differentiation potential was reduced, chon-
drogenic differentiation was not affected. The cells were
more sensitive to the drug than the lung fibroblasts they
were compared with. However, there were no changes to
cell morphology, surface marker expression and the abil-
ity to migrate and adhere. It was also found that the
MSCs could repair the DNA breaks to some extent; thus,
the main proposed mechanism of cell death was via free
radical damage.[34]
Prevention of mitosis is a mechanism of action expressed
by drugs such as paclitaxel, etoposide, anthracyclines and
cytarabine by means of inhibiting or enhancing the activity
of certain enzymes such as topoisomerase II or arresting
the mitotic cycle. In 1997, Carlo-Stella et al. studied the
effects of acute myeloid leukaemia treatment protocols
including such drugs (idarubicin, daunorubicin and etopo-
side) on the entire bone marrow environment and found
that they left the marrow defective and unable to com-
pletely support haematopoietic progenitors and stromal
cells.[35] This study did not include MSCs nor the mecha-
nism of the damage. However, a later study (Li et al.[36])
measured the effects of etoposide, cytarabine and paclitaxel
Mia Baxter-Holland and Crispin R. Dass
on MSCs, and the results were consistent: reduction in pro-
liferation, apoptosis and lack of recovery after 9 days (re-
tention of lineage potential was not studied). These results
are contradictory to Mueller et al.,[37] who found that
MSCs were indeed resistant to etoposide, retaining prolifer-
ation and lineage potential. Although these cells were trea-
ted for shorter amounts of time, the authors were able to
isolate viable MSCs from the bone marrow of humans trea-
ted with chemotherapy.[37] Mueller et al. also compared
the characteristics of MSCs isolated from the bone marrow
of patients who had been exposed to standard- or high-
dose chemotherapy with those from unexposed bone mar-
row; no obvious differences in proliferation capacity and
differentiation potential were found.[37]
Interestingly, Li et al.[36] also found that MSCs suffered
minimal damage and almost complete recovery after expo-
sure to the alkylating agents cyclophosphamide and busul-
fan. The mechanism of action of these drugs involves
irreversibly attaching an alkyl group to the DNA helix
which causes strand breakage and replication inhibition. A
case report of a human patient receiving cyclophosphamide
treatment obtained similar outcomes.[38] MSCs have also
shown resistance in vitro to treatment with drugs such as
cisplatin, camptothecin and vincristine (alkylating agent,
topoisomerase I inhibitor and mitotic inhibitor, respec-
tively); full recovery and maintenance of lineage potential
were observed.[36,37,39] Inconsistency in results suggests that
resistance may be influenced by external factors, such as the
composition of the cell culture medium or duration of
treatment; further in-vivo studies are needed to form con-
clusions that can be extrapolated to humans.
The above findings suggest that the extent of damage to
the MSCs and the bone marrow environment depends on the
mechanism of action of the chemotherapy drug in question,
whether it be DNA damage, mitosis inhibition, enzyme inhi-
bition or free radical generation. There is a lack of data
involving the long-term effects of chemotherapy on in-vivo
MSCs and the bone marrow environment. Additionally, the
precise mechanisms of resistance to chemotherapeutics have
not been pinpointed and require further investigation; it has
been suggested that the cells possess or have the ability to
develop mechanisms for repairing DNA cuts and damage,
that the in-vivo response to acute injury may involve cell
migration, induction of differentiation and proliferation, and
that the apoptotic threshold may be elevated.[34,37,40,41] It has
also been found that antioxidants were able to reduce the
levels of apoptosis in MSCs.[36]
Doxorubicin and stem cells
The complete range of influence doxorubicin has on MSCs
has not yet been clearly elucidated. Due to its multiple and
unique mechanisms of action, changes to MSC health,
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 320–327
Doxorubicin and stem cells
proliferation and lineage potential cannot be confidently
predicted from studies on similar drugs. To make in-vivo
data harder to obtain, doxorubicin is often used in combi-
nation therapy with drugs such as cyclophosphamide,
methotrexate and corticosteroids, making it difficult to
measure the effects of doxorubicin alone.
Negative effects of doxorubicin were reported on MSCs
both in vitro and in vivo (murine) by Oliveira et al.[42]
Responses in the cells included lower proliferation rates,
alkaline phosphatase production deficiency, reduced poten-
tial for differentiation into cardiomyocytes and cytotoxicity
via apoptosis; however, positive and negative cell surface
markers remained the same as the control. The doxoru-
bicin-exposed cells also did not express cardiac troponin T
following cardiomyogenic differentiation induction, unlike
the control group. This hints that the drug’s influence on
MSCs may be partially responsible for its cardiotoxic
adverse effects. Similar cytotoxic responses to doxorubicin
were obtained by Yang et al.,[43] namely cell shrinkage,
apoptosis and enhanced ROS production leading to mito-
chondrial membrane damage. It was also found that dox-
orubicin increased expression of mitogen-activated protein
kinases (MAPK) signalling pathway precisely p38 and jun
N-terminal kinase (JNK), which plays an important role in
induction of inflammatory and apoptotic responses to
oxidative stress, among others.[43,44] When MAPK inhibi-
tors were introduced into culture, lower levels of apoptosis
were observed. Elevated levels of these factors have consis-
tently been reported in other studies of doxorubicin-treated
cells.[45,46] Yang et al.[43] also reported that doxorubicin
increased the expression of p53 and cleaved-caspase-3 pro-
teins, which signalled downstream genes including B-cell
lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) to cause
cellular apoptosis. Thus, one hypothesised reason for apop-
tosis was via ROS activation of phosphorylated p38, p53
and JNK.[43,47] In the same study, the secretion of vascular
endothelial growth factor and insulin-like growth factor 1
(IGF-1) was decreased by doxorubicin. These factors are
involved in the proliferation of and anabolic responses of
types of cells[48] and angiogenesis.[49] While this is a desir-
able effect in reducing tumour size, it could decrease the
ability of MSCs to heal and maintain adult tissues.[43,47,48]
As MSCs have such a high regenerative potential, their
presence and influence have been associated with promo-
tion of tumour growth, such as apoptosis control, vascular
support, suppression of immune response and modulation
of response to cytotoxic therapy.[50,51] MSCs appear to
migrate to injured tissue sites which includes both solid
tumours and the bone marrow in the case of haematologi-
cal malignancies as such tissues often resemble those in
need of repair.[52] MSCs can potentially promote tumour
growth via stimulating angiogenesis in ischaemic tissue,[53]
paracrine secretion of multiple anti-apoptotic factors and
323
Doxorubicin and stem cells
Figure 1 Mesenchymal stem cells promote malignancy survival. TGFb, transforming growth factor b; Th1, helper T cell 1; BCRP, breast cancer resis-
tance protein; STAT3, signal transducer and activator of transcription 3; CCL5, C-C motif chemokine ligand 5; IL-6, interleukin 6; IL-8, interleukin 8.
[Colour figure can be viewed at wileyonlinelibrary.com]
growth factors, and differentiating into carcinoma-asso-
ciated fibroblasts which promote metastasis and drug resis-
tance.[54,55] Results are conflicting in experimental models.
Chen and colleagues[56] reported triple negative breast can-
cer showing increased resistance to doxorubicin upon
interaction with adipose-derived MSCs (ASCs). The mech-
anism of such results involved decreased intracellular dox-
orubicin accumulation within the breast cancer cells due to
increased breast cancer resistance protein (BCRP) expres-
sion, and increased secretion of IL-8 cytokines. MSCs also
appear able to aid breast cancer cells to evade immune sys-
tem attack via increasing helper T cell (Th) Th1 and TGF-
ß1 production.[57] Building upon these findings, a study by
Karnoub et al.[58] showed that the combination of MCSs
with weakly metastatic human breast carcinoma cells led to
a significant increase in the cells’ metastatic potential when
the cells formed a xenograft. Increased secretion of the che-
mokine CCL5 from MSCs led to paracrine responses in the
breast cancer cells, stimulating their motility and metasta-
sis. A study by Tu et al.[59] showed osteosarcoma cells of
the subtypes Saos-2 and U2-OS also displaying improved
survival rates from both doxorubicin and cisplatin treat-
ment when grown in a medium containing MSCs com-
pared to control. Such cells displayed significantly lower
levels of caspase 3/7 activity, thus preventing apoptosis, and
higher activity of IL-6 and STAT3 (signal transducer and
activator of transcription 3), mediators in osteosarcoma
proliferation. Conclusive results were also obtained in vivo
from mouse models.[59] Multiple studies have shown
STAT3 inhibition being to be able to reverse drug (includ-
ing doxorubicin) resistance, suggesting that STAT3 is
important in resistance development.[59–61]
Other experimental models present different outcomes.
No significant changes in doxorubicin sensitivity were dis-
played by A459 lung cancer cells that had been treated in
culture with Wharton’s jelly-derived MSC secretome, the
name given to the immunomodulatory cytokines, growth
factors and chemokines produced by MSCs.[62] It is noted
324 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 320–327
Mia Baxter-Holland and Crispin R. Dass
that only the isolated secretome was used; this suggests the
secretome alone may not be responsible for resistance/sen-
sitivity induction, or may be unable to produce such out-
comes without presence of MSCs themselves. Ryu et al.[63]
and Kucerova et al.[64] observed suppression of human
breast cancer cell growth and increased chemosensitivity to
doxorubicin, respectively, when in contact with ASCs.
Causes of increased sensitivity were unclear. Similar growth
inhibitory responses were expressed when human MSCs
were intravenously injected into mice suffering Kaposi’s
Sarcoma; they migrated to tumour sites, and tumours
decreased in size in a dose-dependent manner.[65] Bergfeld
et al.[66] found that circulating bone marrow MSCs were
incorporated into tumour cells and localised at the invasive
front of tumours, enhancing their expansion and protecting
them from drug-induced apoptosis. No definitive answer
on the effects of MSCs on tumour growth in the presence
of doxorubicin can yet be gleaned from the literature. It
appears that the influence on drug resistance depends on a
multitude of factors including the context of MSC presence
and treatment, and the specific cell type, for example ASCs.
The nature of the tumour also plays a part, whether the cells
are actively dividing or dormant, the type of malignancy
and surrounding stromal cells, and the cellular interactions
within the tumour microenvironment.[64,67] This raises the
question of whether the cytotoxic effect of doxorubicin is
indeed a negative thing; if MSCs aid tumour survival under
exposure to treatment with drugs such as doxorubicin,
toxic effects may not be so undesirable (Figure 1).
Doxorubicin has a wide range of adverse effects includ-
ing immunosuppression, dyspigmentation, gastrointestinal
disturbances leading to severe nausea and vomiting, and
life-threatening cardiotoxicity. The latter typically presents
as acute or insidious cardiomyopathy and heart failure and
is exponentially dose-dependent.[68,69] Anthracycline expo-
sure to the cardiac progenitor cells or MSCs has been pro-
posed as a cause for such toxicity, reducing the body’s
ability to heal and repair the heart.[43,48] Current treatments
Mia Baxter-Holland and Crispin R. Dass Doxorubicin and stem cells

Table 1 Key papers on doxorubicin and mesenchymal stem cells

References Findings

[42] Lower proliferation rates, alkaline phosphatase production deficiency, reduced potential for differentiation into cardiomyocytes
and cytotoxicity via apoptosis
Dox dose = 5 mg/kg per week for 4 weeks
[43] Cell shrinkage, apoptosis and enhanced ROS production lead to mitochondrial membrane damage
Dox dose = 1, 3 and 10 lM
[56] MSCs increased drug resistance in triple negative breast cancer cells
Dox dose = 200 nM, 2 lM
[59] MSC co-culture with osteosarcoma cells displayed improved survival rates against doxorubicin
Dox dose = 10 mg/kg per week for 4 weeks
[64] MSCs cause suppression of human breast cancer cell growth and sensitivity to doxorubicin, respectively
Dox dose = 6.25–100 ng/ml
Administration of MSCs after or during doxorubicin treatment improves cardiac function in animal studies
[72] Dox dose = 3 mg/kg weekly for 6 weeks
[73] Dox dose = 2.5 mg/kg thrice weekly for 2 weeks
ROS, reactive oxygen species; MSCs, mesenchymal stem cells.

include angiotensin-converting enzyme inhibitors, beta-
blockers or heart transplantation.[70] The use of MSCs for
cardio-protection or cardio-regenerative therapy in dox-
orubicin patients has been considered, however such ther-
apy is undertaken with an air of caution due to the
observed tumour-proliferation effects of MSCs in response
to doxorubicin.[71] Several studies of such therapy have
been successful and promising. Administration of bone
marrow-derived MSCs (BMMSCs) 2 weeks after doxoru-
bicin treatment generated significant improvement in left
ventricular function in rabbits.[72] Another study in rats
showed that daily dosing of BMMSCs for 10 days 10 weeks
after doxorubicin treatment improved cardiac contractility
and reduced myocardium fibrosis and left ventricular
diameter.[73] Finally, contradictory to fears that MSCs may
enhance tumour proliferation in the presence of doxoru-
bicin, Oliveira et al. observed a partial cardioprotective
effect in rats when treated with MSCs during doxorubicin
therapy.[74] However, the duration of the beneficial effect is
not known.
Conclusions
Due to the lack of long-term clinical studies on the conse-
quences on stem cells of chemotherapy, projections of
how doxorubicin may influence a patient’s health post-
treatment are not very clear. Stem cells are of vital
importance in the maintenance and repair of human tis-
sues. Certainly, the literature shows that drugs such as
doxorubicin have the possibility to cause severe and pos-
sibly irreversible damage to the bone marrow environ-
ment and MSCs, via mechanisms such as free radical
damage and induction of apoptotic pathways (sum-
marised in Table 1). Whether this damage is clinically sig-
nificant for the remainder of the patient’s lifetime is not
yet known. MSCs have been shown to lead to tumour
resistance when under treatment with doxorubicin, this
could affect the success of cancer treatment and the use
of MSCs to repair tissues damaged by chemotherapy. Fur-
ther investigation into the mechanisms of resistance to
chemotherapy treatment could shed light on ways to
overcome them.
Declarations
Conflict of interest
The Author(s) declare(s) that they have no conflicts of
interest to disclose.
Acknowledgements
The authors acknowledge support via an Academic50 grant
to CRD.

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