МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН
Cancer metastasis, the process by which cancer cells spread from the primary tumor to distant sites, remains the leading cause of cancer-related deaths. Th s complex process involves a series of steps, including cell detachment, migration, invasion, survival in the circulatory system, extravasation,...
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Experimental Oncology| _version_ | 1868113233287577600 |
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| author | Stepanov, Y. Yakshibaeva, Y. Semenkova, V. Stepanova, L. Solyanik, G. |
| author_facet | Stepanov, Y. Yakshibaeva, Y. Semenkova, V. Stepanova, L. Solyanik, G. |
| author_institution_txt_mv | [
{
"author": "Y. Stepanov",
"institution": "R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, Kyiv, Ukraine"
},
{
"author": "Y. Yakshibaeva",
"institution": "R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, Kyiv, Ukraine"
},
{
"author": "V. Semenkova",
"institution": "Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "L. Stepanova",
"institution": "Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "G. Solyanik",
"institution": "R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Stepanov, Y. |
| baseUrl_str | https://exp-oncology.com.ua/index.php/Exp/oai |
| collection | OJS |
| datestamp_date | 2026-06-15T10:40:21Z |
| description | Cancer metastasis, the process by which cancer cells spread from the primary tumor to distant sites, remains the leading cause of cancer-related deaths. Th s complex process involves a series of steps, including cell detachment, migration, invasion, survival in the circulatory system, extravasation, and colonization of new tissues. A fundamental characteristic of cancer cells is their altered metabolism, often exhibiting increased glucose uptake and a preference for glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect. Th s metabolic shift provides cancer cells with a rapid source of adenosine triphosphate (AtP) and essential biosynthetic intermediates, supporting their rapid growth and proliferation. While early concepts attributed the Warburg effect to mitochon- drial dysfunction, it is now recognized that mitochondria in cancer cells often remain functionally active, including oxidative phosphorylation, and critically regulate tumor progression. Notably, metastatic cells frequently depend on mitochondrial activity, refl cting metabolic plasticity that supports dissemination. Thus, targeting glycolysis–mito- chondria crosstalk may represent a promising antimetastatic therapeutic strategy. Th s review aims to elucidate the mechanisms by which inhibitors of glycolysis and OXPhOS impact cancer cell migration, invasion, and metastasis, and to explore their potential therapeutic applications. |
| doi_str_mv | 10.15407/exp-oncology.2026.01.011 |
| first_indexed | 2026-06-15T01:00:21Z |
| format | Article |
| fulltext |
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 11
Glycolysis inhibitors and their
impact on metastasis
Several inhibitors targeting glycolysis have been in-
vestigated for their potential to impair cancer me-
tastasis. These include sodium oxamate (SO), 2-de-
oxyglucose (2DG), 3-bromopyruvate, and others,
each with distinct mechanisms of action (Fig. 1).
SO inhibits glycolysis by competitively inhibiting
lactate dehydrogenase (LDH), a key enzyme cata-
lyzing the conversion of pyruvate to lactate, there-
by supporting tumor cell proliferation and metas-
tasis [1]. This inhibition disrupts the final step of
glycolysis, reducing the lactate production and
decreasing the regeneration of NAD+, which is es-
Review
C i t a t i o n: Stepanov Y, Yakshibaeva Y, Semenkova V, Stepanova L, Solyanik G. Metabolic inhibitors and their impact on
cancer cell migration, invasion, and metastasis. Exp Oncol. 2026; 48(1): 11-23. https://doi.org/10.15407/exp-oncology.
2026.01.011
© PH “Akademperiodyka” of the NAS of Ukraine, 2026. This is an open access article under the CC BY-NC-ND license
(https://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.15407/exp-oncology.2026.01.011
Y. Stepanov 1, *, Y. Yakshibaeva 1,
V. Semenkova 2, L. Stepanova 2, G. Solyanik 1
1 R.E. Kavetsky Institute of Experimental Pathology,
Oncology and Radiobiology, the National Academy
of Sciences of Ukraine, Kyiv, Ukraine
2 Institute of Biology and Medicine, Taras Shevchenko
National University of Kyiv, Kyiv, Ukraine
* Correspondence: E-mail: lestehprom@gmail.com
Metabolic Inhibitors and their
Impact on Cancer Cell Migration,
Invasion, and Metastasis
Cancer metastasis, the process by which cancer cells spread from the primary tumor to distant sites, remains the
leading cause of cancer-related deaths. This complex process involves a series of steps, including cell detachment,
migration, invasion, survival in the circulatory system, extravasation, and colonization of new tissues. A fundamental
characteristic of cancer cells is their altered metabolism, often exhibiting increased glucose uptake and a preference
for glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect. This metabolic shift
provides cancer cells with a rapid source of adenosine triphosphate (ATP) and essential biosynthetic intermediates,
supporting their rapid growth and proliferation. While early concepts attributed the Warburg effect to mitochon-
drial dysfunction, it is now recognized that mitochondria in cancer cells often remain functionally active, including
oxidative phosphorylation, and critically regulate tumor progression. Notably, metastatic cells frequently depend on
mitochondrial activity, reflecting metabolic plasticity that supports dissemination. Thus, targeting glycolysis–mito-
chondria crosstalk may represent a promising antimetastatic therapeutic strategy. This review aims to elucidate the
mechanisms by which inhibitors of glycolysis and OXPHOS impact cancer cell migration, invasion, and metastasis,
and to explore their potential therapeutic applications.
Keywords: glycolysis inhibitors, oxidative phosphorylation inhibitors, migration, invasion, metastasis.
12 ISSN 1812-9269. Experimental Oncology 48 (1). 2026
Y. Stepanov, Y. Yakshibaeva, V. Semenkova, L. Stepanova, G. Solyanik
sential for the continuation of glycolysis, ultimate-
ly resulting in reduced ATP levels [2]. Studies
have shown that SO inhibits the viability of vari-
ous cancer cell lines, including gastric, cervical,
breast cancer cells, and others [3—8]. In gastric
cancer cells, it induces protective autophagy [3].
Furthermore, SO treatment can lead to the en-
hanced production of reactive oxygen species
(ROS), potentially contributing to cellular stress
and inhibition of metastasis. It was also shown to
inhibit the AKT-mTOR signaling pathway, which
is crucial for cell growth and proliferation in many
cancers [3]. In cervical and breast cancer cell lines,
SO decreases LDH-A levels and activity, directly
confirming its mechanism of action, and reduces
superoxide dismutase (SOD) activity and the lev-
els of reduced glutathione (GSH), further sup-
porting an increase in ROS [4]. In nasopharyngeal
carcinoma cells, LDH inhibition by SO induced a
G2/M cell cycle arrest and promoted apoptosis [5].
Notably, SO was found to decrease cell viability
and migration in colorectal cancer cells by reduc-
ing lactate levels [6]. In esophageal cancer, it im-
pairs TNF-α-dependent tumor cell migration [7],
suggesting a role in counteracting inflamma-
tion-driven metastasis. Additionally, SO inhibits
cell growth, suppresses tumor invasion, and in-
duces apoptosis in gastric cancer cells [8]. Our re-
cent studies have shown that the cytostatic effect
of SO, observed under adherent growth condi-
tions, persisted for up to 72 h after the transition
to attachment-independent growth [9]. The clin-
ical application of SO is limited to its low specific-
ity, as it inhibits not only LDH-A but also other
LDH isoforms, potentially disturbing metabolic
balance in normal tissues. SO is a highly polar
compound with restricted cell permeability, which
reduces its intracellular efficacy. Its therapeutic ef-
fectiveness is further compromised by the meta-
bolic plasticity of tumors [10]. Upon LDH-A
blockade, cancer cells can shift to oxidative phos-
phorylation (OXPHOS) or alternative pathways
such as glutaminolysis and fatty acid β-oxidation.
Moreover, SO demonstrates a limited efficacy
against migration and invasion: while glycolytic
inhibition attenuates proliferation, tumor cells
may maintain their motility through mitochon-
drial ATP production [10, 11].
Fig. 1. Glycolysis inhibitors and their impact on metastasis. The scheme illustrates how inhibition of glycolysis affects
tumor progression and metastasis. The key inhibitors — sodium oxamate, 2-deoxyglucose (2-DG), and 3-bromopyru-
vate (3-BP) — target enzymes involved in glucose metabolism, leading to ATP depletion, reduced lactate production,
increased ROS generation, and disruption of signaling pathways. These effects suppress cancer cell proliferation, migra-
tion, and invasion. The main disadvantages of glycolysis inhibitors include low selectivity, systemic toxicity, metabolic
adaptation of tumor cells (switching to OXPHOS), and limited efficacy due to tumor heterogeneity and compensatory
metabolic pathways
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 13
Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis
2-Deoxyglucose (2DG) is another well-studied
glycolysis inhibitor that, due to its structural sim-
ilarity to glucose, competitively inhibits hexoki-
nase and suppresses early glycolysis [12]. This
leads to reduced ATP production and accumula-
tion of 2-deoxy-glucose 6-phosphate (2DG-6P).
Research shows that 2-DG inhibits aggressive tri-
ple-negative breast cancer cells by targeting their
reliance on glycolysis and by reversing the cancer
stem cell (CSC) phenotype. 2-DG enters cancer
cells and then 2-DG-6P blocks glycolysis and
causes a deficiency of energy. This metabolic
blockade also reduces the aggressive characteris-
tics of CSCs, such as their migration, invasion,
and resistance to programmed cell death (anoi-
kis) [13, 14]. Non-cytotoxic doses of 2-DG effec-
tively diminished invasiveness in cell lines like
MDA-MB-231, SUM149, and HCC1937 without
causing cell death, suggesting 2-DG could be
used as an adjuvant to target metastasis [13].
While effectively inhibiting glycolysis, 2DG acti-
vates multiple prosurvival pathways through IG-
F1R, which can potentially limit its efficacy as a
single agent [15]. Furthermore, 2DG alters
N-linked glycosylation, a process that can affect
the function of proteins involved in cancer pro-
gression and metastasis [12]. Despite these com-
plexities, 2DG has demonstrated the ability to in-
hibit proliferation, migration, and invasion of
various cancer cell types, including colorectal and
colon cancer [16]. It can also enhance the oncoly
tic effect of Coxsackie virus [17] and potentially
boost T cell cytotoxicity [18], suggesting its util-
ity in combination therapies. The low therapeutic
selectivity of 2DG leads to glycolysis inhibition in
both tumor and non-tumor cells, resulting in tox-
icity to normal tissues, particularly highly glyco-
lytic cells, such as neurons and cardiomyocytes
[19]. The treatment with 2DG induces the com-
pensatory enhancement of the mitochondrial res-
piration, enabling tumor cells to adapt and main-
tain their migratory capacity. Moreover, its im-
pact on the invasion appears insufficient, given
that cytoskeletal and adhesion mechanisms are
only partially dependent on the glucose availabil-
ity. This is further supported by studies demon-
strating that even under glucose-limiting condi-
tions, cancer cells can adapt their metabolic path-
ways to utilize alternative energy sources, such as
glutamine or fatty acids, to maintain cellular
functions necessary for invasion. The redundan-
cy in these pathways ensures that the cells retain
invasive capabilities, albeit potentially at a re-
duced rate [20—22].
3-Bromopyruvate (3-BP) is a more potent
glycolysis inhibitor for selective cancer treatment
that acts by alkylating key glycolytic enzymes,
such as hexokinase-II (HK-II) and glyceralde-
hyde-3-phosphate dehydrogenase [23, 24]. This
leads to a significant reduction in ATP produc-
tion and can also result in ROS generation. 3-BP
has been shown to inhibit proliferation and me-
tastasis in the preclinical models [23] and be able
to disrupt the cytoskeleton, thereby inhibiting
cell migration and colony formation [25]. Nota-
bly, 3-BP exhibits some selectivity for tumor cells
due to their increased glucose consumption and
overexpression of monocarboxylate transporters
and HK-II [26]. However, the therapeutic appli-
cation of 3-bromopyruvate (3‑BP) remains se-
verely limited by its high toxicity and poor selec-
tivity, as the compound induces damage not only
in tumors but also in vital organs, such as the liv-
er and kidneys, at higher doses [27]. It should be
noted that, to date, there have been insufficient
data to fully characterize the pharmacokinetics of
3-BP, including its distribution, metabolism, and
elimination, as previously noted [28]. Further re-
search is essential to evaluate the potential toxi
city of the drug in normal tissues, particularly
those that are highly dependent on mitochondri-
al function and ATP levels. Resistance mecha-
nisms also emerge upon treatment, most notably
through metabolic rerouting toward glutamino-
lysis and fatty acid oxidation following hexoki-
nase blockade [29, 30]. In addition, the antitumor
activity of 3-BP is weakened by the intrinsic en-
ergetic flexibility of migrating cancer cells. Cir-
culating tumor cells (CTCs) and invasive front
populations often display a greater reliance on
mitochondrial metabolism than on glycolysis, en-
abling them to escape glycolytic inhibition [31,
32]. These limitations underscore the need for
next-generation analogs or delivery strategies
that improve stability, enhance selectivity, and ef-
fectively target the metabolic adaptability of ag-
gressive tumor cell subpopulations.
Other glycolysis inhibitors, including lonid-
amine [33, 34], inhibitors of pyruvate kinase, res-
veratrol [35], and various natural products, such
14 ISSN 1812-9269. Experimental Oncology 48 (1). 2026
Y. Stepanov, Y. Yakshibaeva, V. Semenkova, L. Stepanova, G. Solyanik
as kaempferol [36] and cantharidin [37], also
show promise in targeting cancer metabolism and
inhibiting metastasis by affecting different steps
in the glycolytic pathway. The inhibition of gly-
colysis by these agents impairs the specific steps
of metastasis by reducing the energy available for
these processes. Cell detachment, migration, in-
vasion, and colonization require significant ATP
supply, and by disrupting glycolysis, these inhib-
itors can hinder these energy-dependent steps.
Furthermore, the modulation of signaling path-
ways and the tumor microenvironment (TME),
particularly the reduction of lactate production,
can indirectly impede the metastatic cascade.
Similar to other metabolic inhibitors, lonidamine
and resveratrol exhibit low selectivity. Lonid-
amine has been reported to damage mitochondria
in normal cells as well [38]; however, no direct
evidence of cardiotoxicity or neurotoxicity has
been documented in clinical or preclinical studies
specifically for lonidamine. Importantly, lonid-
amine induces ROS, which may not always sup-
press but, in some contexts, rather promote cell
migration and epithelial–mesenchymal transition
(EMT) [39, 40]. Metastatic populations, including
CTCs and cells at the invasive front, are often better
adapted to elevated oxidative stress and may exploit
ROS as a signal for enhanced motility [38]. Resver-
atrol, in addition to its low selectivity, suffers from
poor in vivo bioavailability and is rapidly metab-
olized, which is reflected in low plasma concen-
trations [41]. It displays pleiotropic activity, mod-
ulating a wide range of pathways (including
SIRT1, AMP-activated protein kinase (AMPK),
and NF‑κB), making its biological outcomes diffi-
cult to predict [42]. Resveratrol exerts only weak
and reversible effects on tumor metabolism and
does not induce sustained energetic collapse [43].
Evidence on its role in migration and invasion re-
mains contradictory: while some models report
suppression of EMT, others suggest it may facilitate
stress adaptation and survival [44].
Taken together, metabolic inhibitors such as
SO, 2-DG, 3-BrPA, lonidamine, and resveratrol
possess antitumor potential, yet their major lim-
itations include low selectivity, systemic toxicity,
and the capacity of tumor cells to evade inhibition
through metabolic plasticity. Therefore, an effec-
tive suppression of migration, invasion, and me-
tastasis is likely to require combination strategies
that concurrently target cellular metabolism, key
signaling pathways (EMT, integrins, PI3K/AKT),
and the tumor microenvironment.
Oxidative phosphorylation inhibitors
and their impact on metastasis
Inhibitors of OXPHOS, such as metformin (MTF)
and others, have also demonstrated potential in
combating cancer metastasis (Fig. 2) [45]. MTF, a
widely used anti-diabetic drug, mildly inhibits
mitochondrial complex I, the first complex of the
electron transport chain [46]. This leads to re-
duced ATP production and activation of the-
AMPK-dependent signaling pathway [47]. MTF
has been shown to inhibit cancer invasion and mi-
gration through the AMPK signaling pathway
[48] and to reduce the expression of transcription
factors driving the EMT [49], a crucial process in
metastasis. MTF can induce bioenergetic stress in
cancer cells [47]. Treatment with MTF was asso-
ciated with reduced morbidity and mortality in
non-small cell lung cancer patients [50]. Its anti-
cancer effects can be insulin-dependent and insu-
lin-independent [50]. This energy deficit can im-
pair metastasis. Activation of AMPK by MTF and
its impact on EMT are the key mechanisms by
which it inhibits cancer spread [49]. Inhibitors of
mitochondrial dynamics can also affect cell mi-
gration and invasion by disrupting the proper dis-
tribution and function of mitochondria within the
cell [46, 49, 51—54].
Other OXPHOS inhibitors include potent com-
plex I inhibitors like IACS-010759 [55], mito-
chondrial electron transport inhibitors like NDU-
FA4L2 [56], TPP+ (triphenylphosphonium-target-
ed compounds)-based drugs [57], oligomycin A
[58], and antimycin A [59], and inhibitors of mi-
tochondrial dynamics like Mdivi-1(inhibitor of
DRP1) mediated mitochondrial fission [60].
These agents target different aspects of mitochon-
drial function and have shown promise in pre-
clinical studies for inhibiting tumor growth and
metastasis. Notably, metastatic colorectal cancer
has been found to rely heavily on mitochondrial
metabolism, suggesting that OXPHOS inhibitors
could be particularly effective in this cancer type
[54]. While inhibitors of OXPHOS and mitochon-
drial functions (including MTF, IACS-010759,
NDUFA4L2 inhibitors, TPP+-based compounds,
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 15
Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis
metastatic activity [62]. Many cancer cells adapt
to OXPHOS inhibition by upregulating glycolysis
or glutamine metabolism, thereby preserving mo-
tility and invasion [51, 63—64]. Consequently,
MTF typically exerts stronger effects on prolife
ration than on invasion or migration in many
models. Its effectiveness is also highly dependent
on the genetic background of tumor cells, includ-
ing the LKB1/AMPK status [65]. The drawbacks
of other OXPHOS or mitochondrial dynamics in-
Fig. 2. OXPHOS inhibitors and their impact on metastasis. This scheme shows how mitochondrial OXPHOS inhibitors
suppress tumor progression. The inhibition of the electron transport chain, particularly complex I, by metformin and
IACS-010759, reduces ATP production and activates AMPK, suppressing EMT, invasion, and migration. Other agents
increase ROS, inducing oxidative stress and apoptosis. However, their use is limited by low selectivity, systemic toxicity,
metabolic compensation, and potential activation of pro-metastatic pathways (NF-κB, MAPK, EMT)
oligomycin A, antimycin A, and Mdivi-1) show
promise in suppressing tumor growth, they also
possess significant limitations that restrict their
application in antimetastatic therapy. In particu-
lar, MTF requires suprapharmacological concen-
trations to inhibit tumor OXPHOS in vitro, while
clinically achievable doses are often insufficient
[61]. Moreover, systemic metabolic effects such as
AMPK activation and reduced hepatic gluconeo-
genesis complicate the interpretation of its anti-
16 ISSN 1812-9269. Experimental Oncology 48 (1). 2026
Y. Stepanov, Y. Yakshibaeva, V. Semenkova, L. Stepanova, G. Solyanik
hibitors (IACS-010759, NDUFA4L2 inhibitors,
TPP+-based compounds, oligomycin A, antimy-
cin A, Mdivi-1) parallel those of MTF. Tumor cells
frequently develop resistance to these agents due
to their intrinsic metabolic plasticity, which en-
ables them to switch between OXPHOS, glycoly-
sis, fatty acid oxidation, and glutaminolysis [63,
64]. Furthermore, OXPHOS inhibitors induce sys-
temic toxicity, as mitochondria are indispensable
for energy production in vital tissues such as the
heart, brain, and skeletal muscle. Although these
agents can increase ROS production and trigger
apoptosis, ROS may also activate pro-metastatic
signaling pathways, including NF-κB, MAPK, and
EMT [40, 66]. The heterogeneity of tumors fur-
ther complicates therapeutic outcomes, since met-
astatic subclones often differ in their reliance on
OXPHOS. Importantly, inhibitors of OXPHOS or
mitochondrial dynamics reduce proliferation but
do not directly target key metastatic processes
such as adhesion, EMT, or extracellular matrix re-
modeling. Finally, several OXPHOS inhibitors, in-
cluding IACS-010759, MTF, and phenformin,
have been associated with severe adverse effects,
most notably lactic acidosis [55, 67].
Thus, the disadvantages of OXPHOS and mito-
chondrial dynamics inhibitors (MTF, IACS-
010759, NDUFA4L2 inhibitors, TPP+-based com-
pounds, oligomycin A, antimycin A, Mdivi-1) in
tumor growth suppression include low selectivity,
systemic toxicity, metabolic compensation, and
paradoxical pro-invasive effects mediated through
ROS and metabolic adaptation. The heterogeneous
toxicity profiles of these agents highlight the im-
portance of carefully assessing the risk–benefit ra-
tio for each inhibitor and developing more target-
ed compounds with reduced adverse effects [68].
Findings from studies on OXPHOS and mitochon-
drial dynamics inhibitors support the conclusion
that combined targeting of tumor metabolism, sig-
naling pathways, and the TME is a more rational
strategy for anti-metastatic therapy.
Combined use of glycolysis and
oxidative phosphorylation inhibitors
Simultaneously targeting both glycolysis and
OXPHOS has emerged as a promising strategy to
overcome the metabolic plasticity of cancer cells
and enhance antitumor efficacy [69]. This dual
inhibition can lead to a synergistic antitumor ef-
fect by creating a more profound energy depletion
and preventing cancer cells from compensating
for the inhibition of one pathway by upregulating
the other [70] (Fig. 3). The combination can block
the metabolic switch from OXPHOS to glycolysis
that might occur when only one pathway is tar-
geted [70]. Furthermore, it can enhance the anti-
tumor effect of OXPHOS inhibitors by limiting
the glycolytic backup and increasing the ROS pro-
duction, leading to oxidative stress and cell death
[70]. In some contexts, this combined approach,
when used with radiotherapy, has shown the po-
tential to overcome PD-1 resistance and enhance
antitumor immunity [71]. Given that cancer cells
can access a hybrid metabolic state, where both
glycolysis and OXPHOS coexist, targeting both
pathways simultaneously is a rational therapeutic
strategy [72]. Inhibiting one pathway alone might
trigger compensatory activation of the other,
highlighting the importance of dual inhibition for
achieving a more profound and sustained meta-
bolic disruption. This comprehensive energy de-
pletion can significantly hinder cancer cell sur-
vival and metastatic potential.
Combining glycolysis inhibitors
with other antimetastatic therapies
Combining glycolysis inhibitors with conventional
cancer therapies such as chemotherapy, radiother-
apy, and immunotherapy has shown potential to
enhance their efficacy against metastasis. Glycoly-
sis inhibitors can synergize with chemotherapy by
targeting the metabolic adaptations that lead to
drug resistance and by normalizing the TME,
thereby improving drug penetration [73, 74].
They can also enhance the sensitivity of cancer
cells to radiotherapy by impairing energy-depen-
dent repair mechanisms and by reversing hypoxia
and reducing PD-L1 expression [71]. The key
concept is that radiotherapy requires cellular en-
ergy (ATP) to support DNA repair processes; in-
hibition of glycolysis depletes ATP levels in tu-
mor cells and thereby enhances their radiosensi-
tivity. In addition, normalization of tumor
hypoxia — through the suppression of the glyco-
lytic flux and lactate accumulation — improves
radiation efficacy by promoting reoxygenation
and reducing hypoxia-induced radioresistance.
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 17
Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis
Preclinical and early clinical trials demonstrated
that 2-DG selectively sensitizes tumor cells to ra-
diation by exploiting their elevated glycolytic
flux, while sparing normal tissues that rely more
on oxidative metabolism [75]. These studies re-
ported that combining 2-DG with radiotherapy
led to enhanced tumor regression and delayed re-
growth in glioma and head-and-neck carcinoma
Fig. 3. Combined use of glycolysis and OXPHOS inhibitors against metastasis. The scheme illustrates the synergistic
anti-tumor effects of simultaneously targeting glycolysis and mitochondrial OXPHOS. The dual metabolic inhibition
prevents compensatory metabolic switching, causes ATP depletion, and increases ROS, leading to oxidative stress and
tumor cell death. This strategy suppresses migration and metastasis while also modulating the tumor microenviron-
ment, enhancing radiotherapy and chemotherapy responses, reducing PD-1/PD-L1 signaling, and promoting antitumor
immune activity
18 ISSN 1812-9269. Experimental Oncology 48 (1). 2026
Y. Stepanov, Y. Yakshibaeva, V. Semenkova, L. Stepanova, G. Solyanik
models, associated with depletion of ATP, inhibi-
tion of DNA repair enzymes, and accumulation
of oxidative damage. Clinical phase I/II trials in
patients with glioblastoma confirmed the feasi-
bility and tolerability of such combination regi-
mens [75]. Mechanistically, glycolytic inhibition
by 2-DG leads to energy deprivation and redox
imbalance. The reduced glycolytic flux limits
NADPH regeneration through the pentose phos-
phate pathway, impairing antioxidant defenses
and facilitating radiation-induced ROS accumu-
lation. Elevated ROS levels cause oxidative DNA
lesions and mitochondrial dysfunction, amplify-
ing radiation cytotoxicity. Moreover, 2-DG re-
duces the repair of double-strand breaks by
downregulating key repair proteins (Ku70/80,
DNA-PKcs), thereby prolonging DNA damage
signaling and promoting apoptosis.
Recent investigations have extended these fin
dings to LDH-A inhibition by SO, which blocks
conversion of pyruvate to lactate and disrupts
NAD+ recycling. It has been demonstrated that
SO markedly enhances the radiosensitivity of
lung and colorectal cancer cells both in vitro and
in xenograft models [76]. LDH-A inhibition in-
duced a metabolic shift toward mitochondrial
OXPHOS, leading to overproduction of mito-
chondrial ROS and oxidative stress. This increase
in ROS augmented radiation-induced DNA dam-
age (γH2AX foci) and apoptosis, while suppres-
sion of lactate reduced the antioxidant buffering
capacity of the tumor microenvironment. Nota-
bly, the combination of SO and irradiation sup-
pressed the clonogenic survival more effectively
than either treatment alone, and the effect was ab-
rogated by ROS scavengers such as N-acetylcys-
teine, confirming the central role of oxidative
stress in this synergistic interaction. Beyond ROS
generation, SO-mediated ATP depletion appears
to impair ATP-dependent DNA repair pathways
and the activity of hypoxia-inducible factor-1α
(HIF-1α), reducing the hypoxia-driven radiore-
sistance commonly observed in solid tumors.
This dual effect — metabolic collapse and redox
imbalance — renders LDH-A inhibition a prom-
ising strategy for radiosensitization. Additional
studies support the concept that targeting LDH-A
enhances radiotherapy outcomes and reduces tu-
mor repopulation between irradiation fractions
[77, 78]. Collectively, these findings demonstrate
that interfering with glycolytic metabolism —
either by blocking upstream glucose utilization
with 2-DG or downstream lactate production
with SO — potentiates radiotherapy efficacy
through converging mechanisms: ATP depletion,
oxidative stress amplification, inhibition of DNA
repair, and TME reoxygenation. Given the tu-
mor-selective reliance on aerobic glycolysis (the
Warburg effect), these strategies offer a rational
approach to overcome radioresistance and im-
prove therapeutic indices in solid tumors, includ-
ing lung and colorectal carcinomas.
Recent preclinical studies have shown that tar-
geting glycolysis can significantly reshape the im-
munosuppressive TME, consequently enhancing
the efficacy of immunotherapy. For example,
pharmacologic inhibition of LDH reduces lactate
production, which, in turn, alleviates acidosis in
the TME; this has been demonstrated to reverse
immune suppression by increasing the cytotoxic
T cell function and reducing regulatory T cell
(Treg) activity in murine tumor models [79, 80].
It was shown that LDH inhibition decreases tu-
mor cell glucose uptake and proliferation while
boosting glucose availability in the TME, which
enhances the infiltration and activation of effec-
tor T cells and impairs Treg-mediated suppres-
sion. Moreover, recent work has combined glycol-
ysis inhibition with immunotherapy. In nanoplat-
form-based studies, the agents that deplete lactate
in the tumor (e.g., lactate oxidase-based systems
or inhibitors of lactate production/efflux) have
been shown to shift macrophage polarization to-
ward the M1 phenotypes and increase NK cell
and cytotoxic T lymphocyte infiltration and ac-
tivity [81]. For instance, an oxygen-generating
nanoplatform combining lactate depletion with
sonodynamic therapy promoted M1 macrophage
polarization, improved antigen presentation by
dendritic cells, and enhanced subsequent antitu-
mor immune responses. Thus, inhibition of gly-
colysis and reduction of lactate production exert
not only direct cytotoxic effects on tumor cells
but also profoundly remodel the immunosup-
pressive TME. Suppression of LDH-A or lactate
transporters normalizes extracellular pH, in-
creases glucose availability for effector T lympho-
cytes, reduces the activity of Tregs and M2 mac-
rophages, and enhances the antitumor immune
response. Therefore, metabolic reprogramming
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 19
Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis
of the TME through glycolytic targeting rep-
resents a promising approach to improving the
efficacy of immunotherapy and combination
treatments for malignant tumors.
The synergistic effects observed highlight the
fundamental vulnerability of cancer cells related to
their altered metabolism, making metabolic target-
ing a potentially useful strategy to enhance existing
antimetastatic therapies. Furthermore, the ability
of glycolysis inhibitors to modulate the TME ap-
pears critical for improving the outcomes of com-
bination treatments. However, careful investigation
is needed to determine the optimal combinations,
timing, and dosages to maximize therapeutic ben-
efit while minimizing toxicities.
Conclusion and future
perspectives
Inhibitors of glycolysis and OXPHOS have dem-
onstrated significant potential in preclinical stud-
ies for impairing cancer cell migration, invasion,
and metastasis by disrupting energy production
and modulating key signaling pathways. The com-
bined use of these inhibitors often results in syn-
ergistic effects, overcoming the metabolic plastic-
ity of cancer cells. Furthermore, these metabolic
inhibitors can enhance the efficacy of convention-
al cancer therapies like chemotherapy, radiother-
apy, and immunotherapy. However, the clinical
application of some of these agents is limited by
their side effects. Future research should focus on
developing more specific and less toxic inhibitors,
optimizing combination therapies, and identify-
ing biomarkers to predict patient response. Inves-
tigating novel drug delivery systems to enhance
tumor-specific accumulation of these metabolic
inhibitors is also crucial for improving their ther-
apeutic index and ultimately translating these
promising findings into effective treatments for
metastatic cancer.
Funding
This work was funded by the research program of
the NAS of Ukraine “The Role of Lactate Dehydro-
genase in the Survival and Dissemination of Meta-
statically Active Cells” (0121U113838).
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Submitted: February 02, 2026
ISSN 1812-9269. Experimental Oncology 48 (1). 2026 23
Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis
Ю. Степанов 1, Ю. Якшибаєва 1,
В. Семенкова 2, Л. Степанова 2, Г. Соляник 1
1 Інститут експериментальної патології, онкології та радіобіології
ім. Р.Є. Кавецького Національної академії наук України, Київ, Україна
2 Інститут біології та медицини Київського національного університету
ім. Тараса Шевченка, Київ, Україна
МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ,
ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН
Метастазування — процес, за допомогою якого ракові клітини поширюються з первинної пухлини у віддалені
ділянки, залишається основною причиною смерті онкологічних хворих. Цей процес включає відшарування
клітин, міграцію, інвазію, виживання в системі кровообігу, екстравазацію та колонізацію нових тканин. Фун-
даментальною характеристикою ракових клітин є їхній змінений метаболізм, який часто демонструє підви-
щене споживання глюкози та перевагу гліколізу навіть за наявності кисню, явище, відоме як ефект Варбурга.
Цей метаболічний зсув забезпечує ракові клітини швидким джерелом аденозинтрифосфату та необхідних
біосинтетичних проміжних продуктів, що підтримує їхній швидкий ріст та проліферацію. Хоча ранні теорії
вважали дефект мітохондріального окисного фосфорилювання причиною ефекту Варбурга, зараз визнано,
що мітохондрії в ракових клітинах часто функціональні та відіграють вирішальну роль у різних клітинних
процесах. Примітно, що метастатичні клітини часто демонструють залежність від мітохондріального дихання
та окисного фосфорилювання, що свідчить про потенційну метаболічну адаптацію, яка стимулює прогресу-
вання раку. Цей огляд розглядає механізми, за допомогою яких інгібітори гліколізу та окисного фосфорилю-
вання впливають на міграцію, інвазію та метастазування пухлинних клітин, а також висвітлює перспективи
їх терапевтичного застосування.
Ключові слова: інгібітори гліколізу, інгібітори окисного фосфорилювання, міграція, інвазія, метастазування.
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| id | oai:ojs2.ex.aqua-time.com.ua:article-613 |
| institution | Experimental Oncology |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-06-16T01:00:10Z |
| publishDate | 2026 |
| publisher | PH Akademperiodyka |
| record_format | ojs |
| resource_txt_mv | exp-oncologycomua/4a/a7f0bb57dc0b84c035a8029902b3cd4a.pdf |
| spelling | oai:ojs2.ex.aqua-time.com.ua:article-6132026-06-15T10:40:21Z Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН Stepanov, Y. Yakshibaeva, Y. Semenkova, V. Stepanova, L. Solyanik, G. інгібітори гліколізу, інгібітори окисного фосфорилювання, міграція, інвазія, метастазування glycolysis inhibitors, oxidative phosphorylation inhibitors, migration, invasion, metastasis Cancer metastasis, the process by which cancer cells spread from the primary tumor to distant sites, remains the leading cause of cancer-related deaths. Th s complex process involves a series of steps, including cell detachment, migration, invasion, survival in the circulatory system, extravasation, and colonization of new tissues. A fundamental characteristic of cancer cells is their altered metabolism, often exhibiting increased glucose uptake and a preference for glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect. Th s metabolic shift provides cancer cells with a rapid source of adenosine triphosphate (AtP) and essential biosynthetic intermediates, supporting their rapid growth and proliferation. While early concepts attributed the Warburg effect to mitochon- drial dysfunction, it is now recognized that mitochondria in cancer cells often remain functionally active, including oxidative phosphorylation, and critically regulate tumor progression. Notably, metastatic cells frequently depend on mitochondrial activity, refl cting metabolic plasticity that supports dissemination. Thus, targeting glycolysis–mito- chondria crosstalk may represent a promising antimetastatic therapeutic strategy. Th s review aims to elucidate the mechanisms by which inhibitors of glycolysis and OXPhOS impact cancer cell migration, invasion, and metastasis, and to explore their potential therapeutic applications. Метастазування — процес, за допомогою якого ракові клітини поширюються з первинної пухлини у віддалені ділянки, залишається основною причиною смерті онкологічних хворих. Цей процес включає відшарування клітин, міграцію, інвазію, виживання в системі кровообігу, екстравазацію та колонізацію нових тканин. Фун- даментальною характеристикою ракових клітин є їхній змінений метаболізм, який часто демонструє підви- щене споживання глюкози та перевагу гліколізу навіть за наявності кисню, явище, відоме як ефект Варбурга. Цей метаболічний зсув забезпечує ракові клітини швидким джерелом аденозинтрифосфату та необхідних біосинтетичних проміжних продуктів, що підтримує їхній швидкий ріст та проліферацію. Хоча ранні теорії вважали дефект мітохондріального окисного фосфорилювання причиною ефекту Варбурга, зараз визнано, що мітохондрії в ракових клітинах часто функціональні та відіграють вирішальну роль у різних клітинних процесах. Примітно, що метастатичні клітини часто демонструють залежність від мітохондріального дихання та окисного фосфорилювання, що свідчить про потенційну метаболічну адаптацію, яка стимулює прогресу- вання раку. Цей огляд розглядає механізми, за допомогою яких інгібітори гліколізу та окисного фосфорилю- вання впливають на міграцію, інвазію та метастазування пухлинних клітин, а також висвітлює перспективи їх терапевтичного застосування. PH Akademperiodyka 2026-06-14 Article Article application/pdf https://exp-oncology.com.ua/index.php/Exp/article/view/613 10.15407/exp-oncology.2026.01.011 Experimental Oncology; Vol. 48 No. 1 (2026): Experimental Oncology; 11-23 Експериментальна онкологія; Том 48 № 1 (2026): Експериментальна онкологія; 11-23 2312-8852 1812-9269 10.15407/exp-oncology.2026.01 en https://exp-oncology.com.ua/index.php/Exp/article/view/613/458 Copyright (c) 2026 Experimental Oncology https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| spellingShingle | інгібітори гліколізу інгібітори окисного фосфорилювання міграція інвазія метастазування Stepanov, Y. Yakshibaeva, Y. Semenkova, V. Stepanova, L. Solyanik, G. МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title | МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title_alt | Metabolic Inhibitors and their Impact on Cancer Cell Migration, Invasion, and Metastasis |
| title_full | МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title_fullStr | МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title_full_unstemmed | МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title_short | МЕТАБОЛІЧНІ ІНГІБІТОРИ ТА ЇХ ВПЛИВ НА МІГРАЦІЮ, ІНВАЗІЮ ТА МЕТАСТАЗУВАННЯ РАКОВИХ КЛІТИН |
| title_sort | метаболічні інгібітори та їх вплив на міграцію, інвазію та метастазування ракових клітин |
| topic | інгібітори гліколізу інгібітори окисного фосфорилювання міграція інвазія метастазування |
| topic_facet | інгібітори гліколізу інгібітори окисного фосфорилювання міграція інвазія метастазування glycolysis inhibitors oxidative phosphorylation inhibitors migration invasion metastasis |
| url | https://exp-oncology.com.ua/index.php/Exp/article/view/613 |
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