https://doi.org/10.52973/rcfcv-e34367
Received: 15/12/2023 Accepted: 17/01/2024 Published: 30/03/2024
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Revista Científica, FCV-LUZ / Vol. XXXIV, rcfcv-e34367
ABSTRACT
This study was conducted to compare Mebendazole in terms of its
apoptosis–inducing and tubulin–inhibitory effects when combined
with vincristine and paclitaxel, both of which are used in cancer
treatment. Lung broblast cells (MRC–5) and small cell lung carcinoma
(NCI–H209) cell lines were used in the study. Concentrations of
Mebendazole, vincristine, and paclitaxel at 0.5 µM, 1 µM, 1.5 µM,
and 2 µM were separately applied to these cell lines, as well as in
combinations. After the cells were kept in the culture medium for
24 hours following drug administration, cell proliferation, apoptotic
DNA levels, caspase 3, 8, and 9 levels, and in vitro wound healing
experiments were performed. It was determined that Mebendazole
suppressed cell proliferation and cell healing, increased caspase–3,
caspase–8, caspase–9 levels and apoptotic DNA formation in NCI–
H209 cancer lung cells. Compared to the groups given Mebendazole
and vincristine alone, it was observed that cell proliferation was more
suppressed and, the level of apoptosis increased in cancerous cells
in the groups given the combination of the two drugs. According
to the ndings obtained from the present study, it was believe that
Mebendazole may possess therapeutic activity against cancerous lung
cells (NCI–H209) due to its apoptosis–inducing and cell proliferation–
suppressive effects.
Key words: Apoptosis; anti–cancer, Mebendazole, Paclitaxel,
Vincristine
RESUMEN
Este estudio se realizó para comparar el mebendazol en términos
de sus efectos inductores de apoptosis e inhibidores de tubulina
cuando se combina con vincristina y paclitaxel, ambos utilizados en el
tratamiento del cáncer. En el estudio se utilizaron líneas celulares de
broblastos de pulmón (MRC–5) y de carcinoma de pulmón de células
pequeñas (NCI–H209). Se aplicaron concentraciones de mebendazol,
vincristina y paclitaxel a 0,5 µM, 1 µM, 1,5 µM y 2 µM por separado
a estas líneas celulares, así como en combinaciones. Después de
que las células se mantuvieron en el medio de cultivo durante 24
horas después de la administración del fármaco, se realizaron
experimentos de proliferación celular, niveles de ADN apoptótico,
niveles de caspasa 3, 8 y 9 y experimentos de curación de heridas
in vitro. Se determinó que el mebendazol suprimía la proliferación
celular y la curación celular, aumentaba los niveles de caspasa–3,
caspasa–8, caspasa–9 y la formación de ADN apoptótico en células
cancerosas de pulmón NCI–H209. En comparación con los grupos
que recibieron mebendazol y vincristina solos, se observó que la
proliferación celular estaba más suprimida y que el nivel de apoptosis
aumentó en las células cancerosas en los grupos que recibieron la
combinación de los dos fármacos. Según los hallazgos obtenidos en
el presente estudio, debemos creer que el mebendazol puede poseer
actividad terapéutica contra las células cancerosas del pulmón (NCI–
H209) debido a sus efectos inductores de apoptosis y supresores de
la proliferación celular.
Palabras clave: Apoptosis; anticáncer, mebendazol, paclitaxel,
vincristina
Effects of Mebendazole on the Caspase–mediated Apoptosis mechanism in
Cancer cell culture
Efectos del Mebendazol Sobre el Mecanismo de Apoptosis Mediado
por Caspasa en Cultivos de Células Cancerosas
Mahmut Şahin* , Haki Kara
Sivas Cumhuriyet University, Faculty of Veterinary, Department of Pharmacology and Toxicology. Sivas, Türkiye.
Corresponding author: mahmutsahin@cumhuriyet.edu.tr
Mebendazole on Apoptosis mechanism in Cancer / Şahin and Kara _________________________________________________________________
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INTRODUCTION
The fact that drugs used in the treatment of cancer in humans and
animals have serious side effects, and the desired treatment success
is still not achieved in many types of cancer, compels scientists to
search for new strategies and treatment methods in the battle against
cancer. One of these emerging strategies is the investigation of
non–cancer drugs that may exhibit anti–cancer activity when used
in cancer treatments [1, 2].
In numerous studies examining its anti–cancer activity,
Mebendazole has been compared with conventional antineoplastic
drugs. The literature reports that the apoptosis–inducing effects of
Mebendazole, which contribute to its anti–cancer effects, primarily
stem from the destabilization of the tubulin protein an important
component of the cytoskeleton [3, 4, 5].
Paclitaxel acts by stabilizing the microtubulin structure formed
through the combination of tubulin dimers, while vincristine functions
as a microtubulin destabilizer by depolymerizing the microtubulin
protein formed through tubulin dimer polymerization [6, 7]. Both drugs
induce cell death by disrupting the mitotic division in cells undergoing
mitosis [8]. It has been documented in the literature that Mebendazole
exhibits anti–cancer activity by reducing the levels of depolymerized
tubulin [9, 10, 11]. However, there is a need for further information and
studies on the anti–cancer ecacy of mebendazole when combined
with a known antineoplastic drug. Thus, this study aims to evaluate
the anti–cancer activity of Mebendazole by comparing its effects in
combination with vincristine and paclitaxel.
The present study aims to assess the in vitro effects of mebendazole
on cell proliferation, cell healing, apoptosis induction, and caspase 3, 8,
and 9 levels in healthy and cancerous lung cells (MRC–5 and NCI–H209)
MATERIALS AND METHODS
Cell culture and reagents
Human lung broblast cells (MRC–5) and human small cell lung
carcinoma cells (NCI–H209) were obtained from the Cell Culture
Laboratory at HÜKÜK, Alum Institute, Turkey. Dulbecco's Minimum
Essential Medium (Thermo Fisher Scientic, DMEM, USA) was used
for cell culture. The media were supplemented with 10% FBS (Sigma–
Aldrich) and penicillin–streptomycin (100 U·mL
-1
Invitrogen). All cells
were maintained in a standard incubator (Nüve, EC160, Turkey) at 37°C
with 5% CO
2
. Mebendazole (Mbz), Paclitaxel (Pac), and Vincristine (Vin)
were purchased from Abcam in analytical purity (Cambridge, UK).
Cell viability and proliferation assays
Cell viability and proliferation were assessed using the MTT Cell
Proliferation assay (Biovision, Massachusetts, USA). The cells were
counted on a Thoma slide (2×10
4
cells/well), and then treated with
Mbz, Vin, Pac, Vin + Mbz combination, and Pac + Mbz combinations
at doses ranging from 0.5 to 250 µM in 96–well plates. To determine
the number of viable and proliferating cells, absorbance values were
measured using an Epoch Elisa reader (BioTek, Vermont, USA) at a
wavelength of 590 nm. The experiments were repeated three times.
Caspase–3, 8 and 9 experiments
Colorimetric caspase assay kits (Catalog no: K106, K113, K119,
Massachusetts, USA) were utilized to determine the levels of
caspases. The cells were counted (1×10
6
cells/well), and then treated
with Mbz, Vin, Pac, Vin + Mbz combination, and Pac + Mbz combinations
in 96–well plates at a dose range of 0.5–2 µM. After 24 hours of drug
administration, the experiments were conducted following the
experimental protocol. The absorbance values were measured at a
wavelength of 400 nm using an EPOCH ELISA reader (BioTek, Vermont,
USA). The experiment was repeated at least three times.
Apoptotic Deoxyribonucleic acid (DNA) laddern level
Apoptotic DNA levels were determined using an assay kit from
Biovision (Massachusetts, USA). The drug groups were applied to cells
in 96–well plates at a density of 1×10
6
cells/well, and the cells were
incubated for 24 hours. The experiments were conducted following
the protocol provided with the assay kit. At the end of the experiment,
DNA fragments were separated on a 1.2% agarose gel containing
0.5 µg·mL
-1
ethidium bromide, and the gel was analyzed using a UV
transilluminator device (Maestrogene, Hsinchu, Taiwan). The density
of DNA bands was determined using the image analysis program
(Image J 1.48s processing software, National Institutes of Health,
MD, USA). The experiment was repeated at least twice.
In vitro wound healing experiments
To evaluate cell proliferation and cell migration under in–vitro
conditions, a cellular wound healing experiment was conducted
[12, 13]. After the cells were counted (1×10
6
cells/well), they were
seeded into 6–well plates. Once the cells reached full conuence, a
standardized cellular wound was created in each plate by scratching
the monolayer cell layer. Following the application of control and drug
treatments at a dose range of 0.5–2 µM, the cells were incubated
(Thermo Fisher Scientic, DMEM, USA) in serum–free cell media for
24 hours. After the incubation period, the cellular wound areas were
visualized using a light microscope, and the resulting images were
analyzed using the image analysis program (Image J 1.48s processing
software, National Institutes of Health, MD, USA). In this experiment,
only MRC–5 cells were used since NCI–H209 cells were not suitable
for this particular assay due to their suspension nature
Statistical analysis
The experiments were repeated three times, and standard deviations
were calculated. Analysis of variance was performed using a one–way
ANOVA test, and within–group comparisons were conducted using
Tukey's test. A P–value of <0.05 was considered statistically signicant.
RESULTS AND DISCUSSION
Effect on cell viability and proliferation
Upon examining the obtained results, it was observed that cell
proliferation in NCI–H209 cancer cells decreased in all groups
administered with the drugs, depending on the dosage (FIG. 1).
Similar decreases in cell proliferation were also observed in healthy
MRC–5 cells across all treatment groups (FIG. 1). In the groups where
mebendazole was administered solely to healthy lung broblast
cells, cell viability was noted to be higher compared to other groups.
Additionally, the cell viability ratio in healthy lung cells treated with
mebendazole and vincristine was observed to surpass the cell viability
ratios obtained within the corresponding groups in cancer cells.
This implies that the cytotoxic effect of mebendazole, whether
administered alone or in combination with vincristine, is lower on
FIGURE 1. Cell proliferation levels of Mebendazol, Paclitaxel, Vincristine and
their combinations applied at increasing concentrations in cancer cells (A)
and healthy cells (B) by MTT assay. The drugs were applied to the cells at a
dose range of 0.5–250 µM for 24 h. The standard deviations of the obtained
data were calculated. **
P<0.01 compared to the control group; *P<0.05
FIGURE 2. Apoptotic DNA levels (%) found in apoptotic DNA ladder experiments
in cancer cells (A) and healthy cells (B) in drug administered groups. When
compared with the control group, signicant increases in apoptotic DNA levels
were observed in all groups. **
P<0.01; *P<0.05
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healthy cells. As the inhibition of cell proliferation was approximately
50% within the dose range of 0.5–2 µM, the study was continued
within this dosage range.
Apoptosis levels of Mbz, Pac, Vin, and their combinations on
cancerous NCI–H209 and healthy MRC–5 lung cells were determined
using the apoptotic DNA assay. It was observed that apoptotic
DNA levels signicantly increased in both cancer cells (FIG. 2) and
healthy cells (FIG. 2) within a dose–dependent range of 0.5–2 µM
compared to the control group (**P<0.01; *P<0.05). However, when
the increases in apoptotic DNA levels in healthy and cancer cells are
compared, it is observed that the increase in healthy cells in groups
where mebendazole is administered alone is less than that obtained
in cancer cells. Additionally, the increase in the rate of apoptosis
in cancer cells in groups where mebendazole and vincristine are
administered in combination is noteworthy.
Caspase–3 levels showed an increase in all groups receiving the
drugs, following a dose–dependent pattern compared to the control
group. Particularly, the groups treated with Mebendazole in combination
with vincristine and paclitaxel exhibited more signicant increases
in caspase–3 levels in cancerous NCI–H209 cells (FIG. 3). Similarly,
elevated caspase–3 levels were observed in healthy MRC–5 cells
(FIG.3). (**P<0.01; *P<0.05). The increase in groups where mebendazole
and vincristine are administered to cancer cells is more pronounced
compared to other groups. When comparing the groups where
mebendazole is applied alone, it is also observed that the increase in
healthy cells is less than the elevation observed in cancer cells.
FIGURE 3. Caspase–3 levels measured in NCI–H209 cancer cells (A) and MRC–5
healthy lung cells (B) treated with increasing concentrations of the drug
compared to the control group. Caspase–3 levels increased in all groups
compared to the control group (%). **P<0.01; *P<0.05
FIGURE 4. Caspase–8 levels in NCI–H209 cancer cells (A) and MRC–5 healthy
lung cells (B) compared to the control group. Caspase–8 levels increased in
all groups compared to the control group (%). **P<0.01; *P<0.05
Mebendazole on Apoptosis mechanism in Cancer / Şahin and Kara _________________________________________________________________
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A dose–dependent increase in caspase–8 levels was observed in both
cancerous NCI–H209 cells and healthy MRC–5 cells (FIG. 4) compared
to the control group. The increase in caspase–8 levels was consistent
with the increase in caspase–3 levels (FIG. 3). (**P<0.01; *P<0.05).
There was a dose–dependent increase (%) in caspase–9 levels in the
groups treated with drugs compared to the control group. Increased
caspase–9 levels were observed in both cancerous NCI–H209 cells
and healthy MRC–5 cells (FIG. 5) upon administration of Mebendazole
(**P<0.01; *P<0.05).
In vitro
In the cellular wound healing experiments with MRC–5 cells, the
level of wound healing decreased in all treatment groups compared
to the control group, and this decrease was statistically signicant
(FIG. 6) (**P<0.01; *P<0.05). The positive progression of the wound
healing area, as indicated by the plotted data in the image analysis
program, is visually depicted in FIG. 7. In terms of wound healing, the
groups receiving mebendazole alone exhibited the highest levels
of wound recovery. Additionally, in the groups where mebendazole
was administered in combination with vincristine, the wound healing
rate was higher compared to the groups where vincristine was
administered alone.
In this study, we evaluated the effects of mebendazole on cell
proliferation, apoptotic DNA, caspase 3–8–9 levels, and cell healing in
cancerous NCI–H209 and healthy lung cells under in vitro conditions. The
current data showed that mebendazole has a strong antiproliferative
effect on cancer cells, leading to increased caspase 3–8–9 levels
and apoptosis. Furthermore, the combination of Mebendazole
with vincristine demonstrated more effective anti–cancer activity
compared to paclitaxel. The obtained findings suggest that
FIGURE 5. Caspase–9 levels measured in NCI–H209 cancer cells (A) and
MRC–5 healthy lung cells (B) treated with increasing concentrations of drugs
compared to the control group (%). **P<0.01; *P<0.05
FIGURE 6. Wound healing levels achieved on healthy lung cells (MRC–5) treated
with increasing doses of drugs. While cellular wound healing was positive in other
application groups other than P
aclitaxel, cellular wound level showed a negative
course in the groups treated with 1.5 and 2.0 µM Paclitaxel. (**P<0.01; *P<0.05)
FIGURE 7. Wound healing image with positive direction. Plotted images of
the injured area before drug administration (A) and images taken from the
same area after drug trial (B) in the image analyzer. The red areas represent
the plotted wound area, the yellow contour lines represent the wound lip
formation, and the gray areas represent the monolayer layer
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Mebendazole exerts its suppressive effects on cancer cells through
caspase–mediated apoptosis. In healthy MRC–5 cells, an increase
in apoptoze and caspase levels has also been observed. However, it
is noted that the antiproliferative and apoptotic effects obtained in
normal cell groups treated with mebendazole are minimal compared
to the ndings obtained from cancer cells.
Previous studies have reported the antiproliferative, proapoptotic,
antiangiogenic, migration, and metastasis suppressive effects of
Mebendazole in different types of cancer by disrupting tubulin protein
structure and affecting critical steps in cellular processes [3, 4, 14, 15,
16, 17, 18]. The anti–cancer activity of Mebendazole in human lung cells
has been documented [3]. Another study evaluating Mebendazole's
potential anti–cancer effect on lung cells reported that it disrupts
tubulin protein structure and induces apoptosis in cancer cells with
damaged mitotic processes. The study also compared the effectiveness
of Mebendazole with paclitaxel and found no side effects associated
with Mebendazole administration [4]. The disruption of tubulin
polymerization is considered the primary mechanism underlying
Mebendazole's anti–cancer activity in various cancer cells [4, 16, 19].
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Classical anti–neoplastic agents such as paclitaxel and vincristine
exert their anti–cancer effects by targeting tubulin protein [6, 20,
21, 22]. It has been reported in the literature that vincristine, like
mebendazole, inhibits tubulin polymerization [23]. Our study's results
are consistent with these literature sources. Based on our study's
data (FIG. 1), we suggest that mebendazole's antiproliferative effects
on the cancerous lung cell line are closely related to its inhibition of
tubulin polymerization, and the increased antiproliferative activity
in the combination groups with vincristine likely utilizes a similar
mechanism of action.
Apoptosis is dened as a programmed cell death mechanism, vital
for eliminating damaged cells and regulating regular cell proliferation
[24]. Utilizing apoptosis and its mechanisms in cancer treatment is
considered an ideal approach [25]. The observation of apoptotic
DNA fragments in cells undergoing apoptosis serves as a marker to
distinguish necrosis from apoptosis [26]. The increased levels of
apoptotic DNA in cancerous NCI–H209 cells and MRC–5 cells in our
study (FIG. 2) indicate that the antiproliferative effect of mebendazole
in cancer cells is mediated through apoptosis. In the mechanisms
of apoptosis formation, the effector caspase–3 is activated through
intrinsic and extrinsic pathways, initiating the apoptosis process
[27]. The increase in caspase–3 levels observed in both cancerous
and healthy cells in our study (FIG. 3) also suggests that the
antiproliferative effect of mebendazole in cancer cells occurs through
apoptosis. While caspase–8 is crucial for the intrinsic activation of
apoptosis, caspase–9 plays a role in the receptor–mediated extrinsic
pathway [28]. We determined the levels of caspase–8 (FIG. 4) and
caspase–9 (FIG. 5) in the cancerous and healthy cell lines used in
our study. Comparing the caspase–8 and caspase–9 levels obtained
in our study, the increase in caspase–8 levels shows a parallel
trend with the increase observed in the caspase–3 experiments.
Similar increases in caspase–3 and caspase–8 levels indicate that
the increase in apoptotic DNA levels in our study occurred through
the intrinsic pathway. Furthermore, this nding explains that the
increased ecacy in the groups where mebendazole is combined
with vincristine and paclitaxel is not receptor–mediated.
Cellular wound healing assays are used to assess the migration
abilities of cancerous cells under in vitro conditions [13, 29, 30]. In
the present study, the ndings from the wound healing experiment
using healthy MRC–5 cells (FIG. 6) demonstrate that Mebendazole and
vincristine positively enhance wound healing in a dose–dependent
manner. Conversely, high doses of paclitaxel inhibit wound healing and
negatively impact the wound. These results obtained in a healthy cell
line indicate that the combined use of Mebendazole with vincristine
mitigates the undesirable antiproliferative effect of vincristine on
healthy cells.
CONCLUSION
In this study, a dose–dependent decrease in proliferation, an
elevation in caspase levels, and an increase in apoptosis were
observed in both cancerous and healthy lung cells. However, in the
groups treated with mebendazole in healthy cells, these increases
were found to be at a minimal level compared to cancer cells. In
conclusion, based on the data obtained from the current study, it can
be concluded that Mebendazole inhibits cell proliferation in cancerous
cells through intrinsic apoptotic pathways, leading to apoptosis.
Furthermore, the combination of Mebendazole with vincristine
enhances its anti–cancer activity. In healthy cells, however, the
antiproliferative and apoptotic effects of mebendazole are minimal
compared to cancer cells. These ndings suggest that Mebendazole
holds therapeutic potential for cancer treatment. However, further in
vitro and in vivo experiments with diverse cancer types are required
to validate these results.
ACKNOWLEDGEMENT
The authors would like to thank the Department of Veterinary
Pharmacology and Toxicology and Veterinary Virology, Sivas Cumhuriyet
University, Sivas, Türkiye, where the research work was conducted.
Funding
This work was supported by Cumhuriyet University Scientic
Research Projects Coordination Unit (CUBAP, Sivas, Turkey, grant
number: V–065).
Institutional review board statement
Not applicable.
Informed consent statement
Not applicable.
Data availability statement
The data are available by the corresponding author upon.
The authors declare no conict of interest.
Sample availability
Samples of the compounds are available from the authors.
BIBLIOGRAPHIC REFERENCES
[1] Doudican NA, Byron SA, Pollock PM, Orlow SJ. XIAP downregulation
accompanies mebendazole growth inhibition in melanoma
xenografts. Anti–Cancer Drug. [Internet]. 2013; 24(2):181–188.
doi: https://doi.org/f4hm8n
[2] Nygren P, Fryknas M, Agerup B, Larsson R. Repositioning of
the anthelmintic drug mebendazole for the treatment for colon
cancer. J. Cancer Res. Clin. Oncol. [Internet]. 2013; 139:2133–
2140. doi: https://doi.org/f23r3k
[3] Tapas M, Ji–ichiro S, Ramesh R, Roth JA. Mebendazole Elicits
a Potent Antitumor Effect on Human Cancer Cell Lines Both in
Vitro and in Vivo. Clin. Cancer Res. [Internet] 2002 [cited 27 Oct
2023]; 8(9):2963–2969. Available in: https://goo.su/qG52Bi
[4] Sasaki J–i, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay
T. The Anthelmintic Drug Mebendazole Induces Mitotic Arrest
and Apoptosis by Depolymerizing Tubulin in Non–Small Cell
Lung Cancer Cells. Mol. Cancer Ther. [Internet] 2002 [cited 27
Oct 2023]; 1(13):1201–1209. Available in: https://goo.su/rg8MD
[5] Sawanyawisuth K, Williamson T, Wongkham S, Riggins R. Effect of
the antiparasitic drug mebendazole on cholangiocarcinoma growth.
Southeast Asian J. Trop. Med. Public Health. [Internet]. 2014 [cited
19 Oct 2023]; 45(6):1264. Available in: https://goo.su/YQusKKo
_____________________________________________________________________________Revista Cientifica, FCV-LUZ / Vol. XXXIV, rcfcv-e34367
7 of 7
[6] Chu S, Badar S, Morris DL, Pourgholami MH. Potent Inhibition of
Tubulin Polymerisation and Proliferation of Paclitaxel–resistant
1A9PTX22 Human Ovarian Cancer Cells by Albendazole. Anti–
cancer Res. [Internet]. 2009 [cited 19 Oct 2023]; 29(10):3791–
3796. Available in: https://goo.su/Zuoue
[7] Silverman JA, Deitcher SR. Marqibo® (vincristine sulfate liposome
injection) improves the pharmacokinetics and pharmacodynamics
of vincristine. Cancer Chemother. Pharmacol. [Internet]. 2013;
71(3):555–564. doi: https://doi.org/f4q3rg
[8] Jordan M A, Wilson L. Microtubules and actin laments: dynamic
targets for cancer chemotherapy. Curr. Opin. Cell Biol. [Internet].
1998; 10(1):123–130. doi https://doi.org/ddqjbz
[9] Laclette J, Guerra G, Zetina C. Inhibition of tubulin polymerization
by mebendazole. Biochem. Biophy. Res. Commun. [Internet].
1980; 92(2):417–423. doi: https://doi.org/b55p2p
[10] Katiyar S, Gordon V, McLaughlin G, Edlind TJA. Antiprotozoal
activities of benzimidazoles and correlations with beta–tubulin
sequence. Antimicrob. Agents Chemother. [Internet]. 1994;
38(9):2086–2090. doi: https://doi.org/mnqx
[11] Morgan U, Reynoldson J, Thompson RJA. Activities of several
benzimidazoles and tubulin inhibitors against Giardia spp. in
vitro. Antimicrob. Agents. [Internet]. 1993; 37(2):328–331. doi:
https://doi.org/mnpg
[12] Keese CR, Wegener J, Walker SR, Giaever I. Electrical wound–
healing assay for cells in vitro. Proceedings of the National
Academy of Sciences. [Internet]. 2004; 101(6):1554–1559. doi:
https://doi.org/c8mh9w
[13] Rodriguez LG, Wu X, Guan J–L. Wound–healing assay. In: Guan J–L,
editor. Cell Migration. Methods Mol. Biol. Vol. 294. [Internet]. Totowa,
NJ: Humana Press; 2005. p. 23–29. doi: https://doi.org/d4rcbq
[14] Doudican N, Rodriguez A, Osman I, Orlow SJ. Mebendazole
induces apoptosis via Bcl–2 inactivation in chemoresistant
melanoma cells. Mol. Cancer Res. [Internet]. 2008; 6(8):1308–
1315. doi: https://doi.org/dznd4t
[15] Guerini AE, Triggiani L, Maddalo M, Bonù ML, Frassine F, Baiguini A,
Alghisi A, Tomasini D, Borghetti P, Pasinetti N, Bresciani N, Magrini
SM, Buglione M. Mebendazole as a candidate for drug repurposing
in oncology: an extensive review of current literature. Cancers
(Basel). [Internet]. 2019; 11(9):1284. doi: https://doi.org/2xmr
[16] Martarelli D, Pompei P, Baldi C, Mazzoni G. Mebendazole inhibits
growth of human adrenocortical carcinoma cell lines implanted
in nude mice. Cancer Chemother. Pharmacol. [Internet]. 2008;
61(5):809–817. doi: https://doi.org/dq6mzb
[17] Pinto LC, Mesquita FP, Soares BM, da Silva EL, Puty B, Oliveria EH,
Burbano RR, Montenegro RC. Mebendazole induces apoptosis via
C–MYC inactivation in malignant ascites cell line (AGP01). Toxicol.
in Vitro. [Internet]. 2019; 60:305–312. doi: https://doi.org/mnqm
[18] Wang X, Lou K, Song X, Ma H, Zhou X, Xu H, Wang W. Mebendazole
is a potent inhibitor to chemoresistant T cell acute lymphoblastic
leukemia cells. Toxicol. Appl. Pharmacol. [Internet]. 2020;
396:115001. doi: https://doi.org/mnqn
[19] Lai SR, Castello S, Robinson A, Koehler J. In vitro anti‐tubulin
effects of mebendazole and fenbendazole on canine glioma
cells. Vet. Comp. Oncol. [Internet]. 2017; 15(4):1445–1454. doi:
https://doi.org/mnqp
[20] Figueroa–Masot XA, Hetman M, Higgins MJ, Kokot N, Xia Z.
Taxol induces apoptosis in cortical neurons by a mechanism
independent of Bcl–2 phosphorylation. J. NeuroSci. [Internet].
2001; 21(13):4657–4667. doi: https://doi.org/mnqt
[21] Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL,
Ehlhardt WJ, Hall S. Selective metabolism of vincristine in vitro
by CYP3A5. Drug Metab. Dispos. [Internet]. 2006; 34(8):1317–1327.
doi: https://doi.org/cfg8z8
[22] Hayot C, Farinelle S, De Decker R, Decaestecker C, Darro F, Kiss
R, Damme MV. In vitro pharmacological characterizations of
the anti–angiogenic and anti–tumor cell migration properties
mediated by microtubule–affecting drugs, with special emphasis
on the organization of the actin cytoskeleton. Int. J. Oncol.
[Internet]. 2002; 21(2):417–425. doi: https://doi.org/mnqv
[23] Mandel EM, Lewinskimd U, Djaldetti M. Vincristine‐induced
myocardial infarction. Cancer. [Internet]. 1975; 36(6):1979–1982.
doi: https://doi.org/bhms9c
[24] Elmore S. Apoptosis: A Review of Programmed Cell Death.
Toxicol Pathol. [Internet]. 2007; 35(4):495–516. doi: https://
doi.org/b5hgfz
[25] Turgut NH, Armagan G, Kasapligil G, Erdogan MA. Anti–cancer
effects of selective cannabinoid agonists in pancreatic and
breast cancer cells. Bratis. Lek. Listy. [Internet]. 2022;
123(11):813–821. doi: https://doi.org/mnqw
[26] Zhang JH, Xu M. DNA fragmentation in apoptosis. Cell Res. 2000;
10:205–211. doi: https://doi.org/d3dnc3
[27] Wang W, Zhu M, Xu Z, Li W, Dong X, Chen Y, Lin B, Li M. Ropivacaine
promotes apoptosis of hepatocellular carcinoma cells through
damaging mitochondria and activating caspase–3 activity. Biol.
Res. [Internet]. 2019; 52(36):1–10. doi: https://doi.org/gkx6tw
[28] Wu Y, Zhao D, Zhuang J, Zhang F, Xu C. Caspase–8 and caspase–9
functioned differently at different stages of the cyclic stretch–
induced apoptosis in human periodontal ligament cells. PLoS
One. [Internet]. 2016; 11(12):e0168268. doi: https://doi.org/f9gx55
[29] Yarrow JC, Perlman ZE, Westwood NJ, Mitchison TJ. A high–
throughput cell migration assay using scratch wound healing, a
comparison of image–based readout methods. BMC Biotechnol.
[Internet]. 2004; 4:21. https://doi.org/c4nxzh
[30] Maini PK, McElwain S, Leavesley D. Travelling waves in a wound
healing assay. Appl. Math. Lett. [Internet]. 2004; 17(5):575–580.
doi: https://doi.org/dst6pw
