*The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.95556*

**Pathway**

**220**

**Protein ID**

 **Gene**

**Protein name**

**Qvalue**

**Intensity H Intensity L Ratio H/L**

**name**

G3V0I5

Q9UEH5

IPYR2

A0A024QZ30

SDHB

D3DVH1

A0A024R5E5

QCR9

QCR7

QCR1

QCR2

A0A384NPX8

QCR8

 UQCRQ

 UQCRFS1

Cytochrome

 b-c1 complex subunit Rieske,

Cytochrome

 b-c1 complex subunit 8

 UQCRC2

Cytochrome

 b-c1 complex subunit 2,

mitochondrial

mitochondrial

0.00E

79904000

 211540000

 0.34

+00

0.00E

88536000

 237890000

 0.57

+00

 UQCRC1

Cytochrome

 b-c1 complex subunit 1,

mitochondrial

 UQCRB

 UQCR10

 TCIRG1

 SDHC

 Succinate

dehydrogenase

 complex, subunit C, integral membrane protein,

15 kDa, isoform CRAa

V-type proton ATPase subunit a

Cytochrome

Cytochrome

 b-c1 complex subunit 7

 b-c1 complex subunit 9

 SDHB

 Succinate

dehydrogenase

[ubiquinone]

 iron–sulfur

 subunit,

mitochondrial

 0.00E

143030000

 516360000

 0.37

+00

0.00E

68060000

 130150000

 0.46

+00

0.00E

139450000

 227300000

 0.73

+00

0.00E

260330000

 491890000

 0.52

+00

0.00E

208330000

 523300000

 0.37

+00

0.00E

1326400000

 3772100000

 0.43

+00

0.00E

1718400000

3636100000

 0.43

+00

 SDHA

 Succinate

dehydrogenase

[ubiquinone]

 flavoprotein

 subunit,

mitochondrial

 0.00E

1096500000

2950800000

 0.44

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

+00

 PPA2

Inorganic

pyrophosphatase

 2,

mitochondrial

 NDUFV2

 NDUFV1

 NADH

dehydrogenase

24-kDa subunit of complex I (Fragment)

[ubiquinone]

 flavoprotein

 1,

mitochondrial

 0.00E

25550000

 98424000

 0.34

+00

0.00E

120810000

 407130000

 0.33

+00

0.00E

815730000

1743800000

 0.42

+00

**Figure 5.**

*RT-qPCR confirmed the effects of ivermectin on the mRNA expressions of key molecules in the energy metabolism pathways in ovarian cancer cells (a-f). The effects of different concentration of ivermectin (0, 10, 20, and 30 μM) on mRNA expressions of PFKP, PKM, CS, PDHB, IDH2, IDH3A, IDH3B, OGDHL, ND5, ND2, CYTB, UQCRH, MCT1, and MCT4. n = 3. \*p < 0.05, \*\*p < 0.01, \*\*\*p < 0.001. Reproduced from Li et al. [21], with copyright permission from nature springer publisher, copyright 2020.*

with ovarian cancer survival rate. Among 306 EIF4A3-binding mRNAs, the protein expressions of 116 EIF4A3-binding mRNAs and EIF4A3 were found to be inhibited by ivermectin, identified by SILAC quantitative proteomics in ovarian cancer cells treated with and without ivermectin (**Table 2**) [4].

Moreover, TCGA transcriptomics analysis found that 16 lncRNAs had binding sites with EIF4A3 and associated with ovarian cancer survival rate, including SNHG3, HCG15, PDCD4-AS1, KIF9-AS1, ZNRF3-AS1, ZNF674-AS1, LINC00565, SOS1-IT1, WWTR1-AS1, PLCH1-AS1, LINC00517, STARD13-IT1, LEMD1-AS1, AL109767.1, HOXC-AS3, and LBX2-AS1 [23]. Further, RT-qPCR analysis of these 16 lncRNA expressions in ovarian cancer cells treated with ivermectin (0 μM, 10 μM, 20 μM, and 30 μM) compared to control cells, which found 9 lncRNAs (PDCD4- AS1, ZNRF3-AS1, HCG15, KIF9-AS1, LINC00565, ZNF674-AS1, AL109767.1, SOS1- IT1, and LBX2-AS1) were significantly affected by ivermectin (**Figure 7**) [4].

These findings clearly demonstrated that ivermectin regulated lncRNA-EIF4A3 mRNA axis in ovarian cancer cells, and these mRNAs included the key molecules in energy metabolism pathways in ovarian cancer cells.

## **3.8 The prognostic model of ivermectin-related three-lncRNA signature for ovarian cancers identified and optimized by lasso regression**

SOS1-IT1, and LINC00565) (**Figure 8**) [4]. This prognostic model was significantly related to overall survival and clinicopathologic characteristics in ovarian cancer patients [4], which might benefit for prognostic assessment and personalized drug

*Western blot confirmed the effects of ivermectin on the protein expressions of key molecules in the energy metabolism pathways in ovarian cancer cells. n = 3. \*p < 0.05, \*\*p < 0.01, \*\*\*p < 0.001. Reproduced from Li*

therapy toward 3P medicine practice in ovarian cancer.

*et al. [21], with copyright permission from nature springer publisher, copyright 2020.*

*The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer*

*DOI: http://dx.doi.org/10.5772/intechopen.95556*

**Figure 6.**

**223**

Based on those nine ivermectin-mediated lncRNAs in ovarian cancers, survival analysis and lasso regression were used to identify and optimize the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1,

### *The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.95556*

### **Figure 6.**

with ovarian cancer survival rate. Among 306 EIF4A3-binding mRNAs, the protein expressions of 116 EIF4A3-binding mRNAs and EIF4A3 were found to be inhibited by ivermectin, identified by SILAC quantitative proteomics in ovarian cancer cells

Moreover, TCGA transcriptomics analysis found that 16 lncRNAs had binding

These findings clearly demonstrated that ivermectin regulated lncRNA-EIF4A3 mRNA axis in ovarian cancer cells, and these mRNAs included the key molecules in

**3.8 The prognostic model of ivermectin-related three-lncRNA signature for**

Based on those nine ivermectin-mediated lncRNAs in ovarian cancers, survival analysis and lasso regression were used to identify and optimize the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1,

**ovarian cancers identified and optimized by lasso regression**

sites with EIF4A3 and associated with ovarian cancer survival rate, including SNHG3, HCG15, PDCD4-AS1, KIF9-AS1, ZNRF3-AS1, ZNF674-AS1, LINC00565, SOS1-IT1, WWTR1-AS1, PLCH1-AS1, LINC00517, STARD13-IT1, LEMD1-AS1, AL109767.1, HOXC-AS3, and LBX2-AS1 [23]. Further, RT-qPCR analysis of these 16 lncRNA expressions in ovarian cancer cells treated with ivermectin (0 μM, 10 μM, 20 μM, and 30 μM) compared to control cells, which found 9 lncRNAs (PDCD4- AS1, ZNRF3-AS1, HCG15, KIF9-AS1, LINC00565, ZNF674-AS1, AL109767.1, SOS1- IT1, and LBX2-AS1) were significantly affected by ivermectin (**Figure 7**) [4].

*RT-qPCR confirmed the effects of ivermectin on the mRNA expressions of key molecules in the energy metabolism pathways in ovarian cancer cells (a-f). The effects of different concentration of ivermectin (0, 10, 20, and 30 μM) on mRNA expressions of PFKP, PKM, CS, PDHB, IDH2, IDH3A, IDH3B, OGDHL, ND5, ND2, CYTB, UQCRH, MCT1, and MCT4. n = 3. \*p < 0.05, \*\*p < 0.01, \*\*\*p < 0.001. Reproduced from Li*

*et al. [21], with copyright permission from nature springer publisher, copyright 2020.*

treated with and without ivermectin (**Table 2**) [4].

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**Figure 5.**

**222**

energy metabolism pathways in ovarian cancer cells.

*Western blot confirmed the effects of ivermectin on the protein expressions of key molecules in the energy metabolism pathways in ovarian cancer cells. n = 3. \*p < 0.05, \*\*p < 0.01, \*\*\*p < 0.001. Reproduced from Li et al. [21], with copyright permission from nature springer publisher, copyright 2020.*

SOS1-IT1, and LINC00565) (**Figure 8**) [4]. This prognostic model was significantly related to overall survival and clinicopathologic characteristics in ovarian cancer patients [4], which might benefit for prognostic assessment and personalized drug therapy toward 3P medicine practice in ovarian cancer.


**Protein IDs**

**225**

A0A0S2Z4T1 A0A0S2Z3L0

Q8NFH5

Q5T7C4 A0A024R8M4

G3V2D5 A6NMQ3 A0A0J9YYL3

A0A481SVJ4

J3KTF8 P49736 K7EJH0 Q9BRA2

P15531 D3DVA5

B7ZM10

G8JLD3 B2R7W3

C9JJ19 A0A0S2Z4Q4

Q53Y51 A0A024R8U9

Hepatocyte

 growth

factor-regulated

D-dopachrome

Pyrroline-5-carboxylate

 reductase 1,

mitochondrial

decarboxylase

 tyrosine kinase substrate

Phosphoribosyl

Zinc finger protein 36, C3H1 type-like 1

Alpha-endosulfine

Poly(U)-binding-splicing

Matrix-remodeling-associated

Rho DNA replication licensing factor MCM2

Kinetochore

Thioredoxin

Nucleoside

Rho guanine nucleotide exchange factor 2

Exportin-6 ELKS/Rab6-interacting/CAST

Breast carcinoma amplified sequence 2

28S ribosomal protein S34,

mitochondrial

 family member 1

 diphosphate

 kinase A

domain-containing

 protein 17

 protein Spc24

GDP-dissociation

 inhibitor 1

 protein 7

 factor PUF60

pyrophosphate

synthase-associated

 protein 1

Electron transfer flavoprotein

 subunit alpha,

Nucleoporin

High mobility group protein B1

 NUP53

mitochondrial

DNA replication licensing factor MCM3

**Protein names**

**Gene names**

MCM3

ETFA NUP35

HMGB1

PRPSAP1

ZFP36L1

ENSA PUF60

MXRA7

ARHGDIA

MCM2

SPC24

TXNDC17

NME1

ARHGEF2

XPO6 ERC1 BCAS2

MRPS34

HGS DDT PYCR1

 0

 20

 72360000

 265100000

 0.45

0

 36

 259770000

 672160000

 0.45

0

 10

 52165000

 121060000

 0.44

 0

 10

 69862000

 158490000

 0.44

 0

 15

 38190000

 177190000

 0.44

0

 44

 179630000

 428430000

 0.44

0

 7

 7924200

 14822000

 0.44

 0

 16

 26979000

 80246000

 0.44

 0

 20

 312380000

 966090000

 0.43

 0

 38

 745240000

 1.838E+09

 0.43

 0

 7

 91278000

 196000000

 0.43

 0

 90

 937140000

 2.544E+09

 0.43

 0

 56

 1.44E+09

 3.59E+09

 0.42

 0

 2

 4184200

 24167000

 0.42

*The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer*

 0

 135

 468910000

 1.281E+09

 0.42

0

 5

 80231000

 206330000

 0.41

 0

 18

 6238500

 15019000

 0.41

 0

 20

 88227000

 200670000

 0.41

*DOI: http://dx.doi.org/10.5772/intechopen.95556*

 0

 98

 2.916E+09

 1.141E+10

 0.40

 0

 81

 206630000

 398870000

 0.40

0

 44

 623280000

 1.382E+09

 0.40

 0

 187

 1.033E+09

 3.186E+09

 0.40

 **Q-value**

 **Score**

 **Intensity H Intensity L Ratio H/L**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*


### *The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.95556*

**Protein IDs**

**224**

A0A0S2Z4C6

A0A024R7B0 A0A024R9A9 A0A494C101 A0A1W2PNM1

Q496I0 Q149N6

Q15036 J3KN67 Q8WZ82

G3V0I5 J3QLR8

J3KSI8 B4DP80

C9JFE4 Q9Y3B7 Q9Y333

P63261 Q07954 Q68E01 K7EKI4 V9GZ56

Prolow-density

 lipoprotein Integrator complex subunit 3

39S ribosomal protein L4,

U6

snRNA-associated

 Sm-like protein LSm4

mitochondrial

receptor-related

 protein 1

NADH

dehydrogenase

28S ribosomal protein S23,

28S ribosomal protein S7,

NAD(P)H-hydrate

COP9 signalosome

39S ribosomal protein L11,

U6

snRNA-associated

 Sm-like protein LSm2

Actin

 complex subunit 1

mitochondrial

 epimerase

[ubiquinone]

 flavoprotein

 1, mitochondrial

mitochondrial

mitochondrial

 NDUFV1 MRPS23

MRPS7

APOA1BP

GPS1 MRPL11

LSM2 ACTG1

LRP1 INTS3

MRPL4

LSM4

0

 4

 89988000

 217330000

 0.39

 0

 9

 41947000

 121900000

 0.39

 0

 11

 32873000

 113610000

 0.38

0

 5

 3971000

 52428000

 0.38

 0

 212

 3.864E+09

 1.674E+10

 0.38

0

 23

 188570000

 423780000

 0.38

 0

 5

 17279000

 5213500

 0.38

0

 25

 189930000

 447320000

 0.38

 0

 47

 81014000

 347980000

 0.37

 0

 9

 56198000

 98108000

 0.35

 0

 8

 59957000

 127510000

 0.35

 0

 9

 25550000

 98424000

 0.34

Pyruvate

carboxylase;Pyruvate

Hydroxyacyl-coenzyme

Cytochrome

 c oxidase subunit 7A2,

Dedicator of cytokinesis Sorting nexin-17

Tropomyosin

Ovarian

cancer-associated

 gene 2 protein

 alpha-3 chain

 protein 4

 A

dehydrogenase,

mitochondrial

mitochondrial

 carboxylase,

mitochondrial

Serine/threonine-protein

 phosphatase Ubiquitin-like

Ubiquitin-conjugating

 enzyme E2 T

 protein 5

 2B catalytic subunit alpha isoform

**Protein names**

**Gene names**

 PPP3CA

UBL5 UBE2T

PC HADH

COX7A2

DOCK4

SNX17

TPM3 OVCA2

 0

 8

 22175000

 92294000

 0.34

0

 3

 44208000

 225430000

 0.34

 0

 9

 2545600

 64295000

 0.33

 0

 4

 2402200

 12153000

 0.33

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

 0

 10

 223550000

 687660000

 0.32

 0

 11

 85389000

 332200000

 0.30

0

 3

 3454600

 19685000

 0.28

 0

 7

 54580000

 216150000

 0.22

0

 3

 33400000

 156360000

 0.20

 0

 106

 450040000

 2.321E+09

 0.17

 **Q-value**

 **Score**


**Protein IDs**

**227**

Q53HN4

P38919 B4DY09

E9PF19 A0A087WXS7

O43324

Q15717 Q9UMS4

P14324 P28070 Q0VGA5 A0A024RCX8

Q9H8H0

E7EX90 Q05D78 H7C440 Q9Y3U8 Q9UJZ1 Q567R6 Q15084 Q15645 A0A024R6K8

Eukaryotic translation elongation factor 1 epsilon-1

ELAV-like protein 1

Pre-mRNA-processing

Farnesyl Proteasome

 subunit beta type-4

SARS protein

Peptidyl-prolyl

 cis-trans Nucleolar protein 11

Dynactin subunit 1

Double-strand

 break repair protein MRE11A

DIS3-like exonuclease

60S ribosomal protein L36

Stomatin-like

Single-stranded

Protein Pachytene checkpoint

Epididymis

 secretory sperm binding protein

 protein 2 homolog

disulfide-isomerase

 A6

DNA-binding

 protein,

 protein 2,

mitochondrial

mitochondrial

 2

isomerase-like

 1

pyrophosphate

 synthase

 factor 19

DNA

fragmentation

Eukaryotic initiation factor 4A-III

Interleukin

Transducin

 beta-like protein 2

ATPase ASNA1

enhancer-binding

 factor 2

 factor subunit alpha

**Protein names**

**Gene names**

DFFA EIF4A3

ILF2 TBL2 ASNA1

EEF1E1

ELAVL1

PRPF19

FDPS PSMB4

SARS PPIL1 NOL11

DCTN1

MRE11A

DIS3L2

RPL36

STOML2

SSBP1

PDIA6

TRIP13

WARS

 0

 80

 1.769E+09

 2.803E+09

 0.56

 0

 27

 276670000

 492930000

 0.56

 0

 323

 1.201E+10

 2.023E+10

 0.56

 0

 60

 561820000

 1.077E+09

 0.55

 0

 119

 866230000

 1.683E+09

 0.55

 0

 34

 544540000

 770200000

 0.55

 0

 4

 13696000

 21117000

 0.54

 0

 3

 24064000

 56350000

 0.54

 0

 131

 823150000

 1.803E+09

 0.54

 0

 5

 22443000

 80063000

 0.54

0

 10

 122810000

 365070000

 0.53

0

 149

 1.216E+09

 2.647E+09

 0.53

 0

 25

 512090000

 1E+09

 0.52

0

 26

 1.03E+09

 2.078E+09

 0.52

*The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer*

 0

 127

 897150000

 2.364E+09

 0.52

 0

 92

 2.093E+09

 4.32E+09

 0.51

 0

 29

 662460000

 1.236E+09

 0.51

 0

 63

 850190000

 1.755E+09

 0.51

*DOI: http://dx.doi.org/10.5772/intechopen.95556*

0

 28

 109400000

 213970000

 0.50

0

 96

 2.642E+09

 6.06E+09

 0.50

 0

 77

 1.57E+09

 3.534E+09

 0.50

0

 31

 272390000

 539710000

 0.50

 **Q-value**

 **Score**


### *The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.95556*

**Protein IDs**

**226**

Q6FHQ0

P29144 Q9UP83

E9PID8 A0A024R496

Q6IAP9 A0A024RB32

E9PMG1

P28066 I3L2G3 A0A0S2Z4Z0

A8K651 O60506

P42345 A8K878 A0MNN4 A0A024R8B1

Q9UHR4

Q5SRT3 A0A0S2Z5I7

Q13505

J3KS15

Peptidyl-tRNA

 hydrolase ICT1,

mitochondrial

Brain-specific

angiogenesis

Chloride intracellular Ribosome maturation

 protein SBDS

Metaxin-1

 channel protein 1

 inhibitor 1-associated

 protein 2-like protein 1

 BAIAP2L1

CLIC1

SBDS MTX1

ICT1

 0.01

 2

 29017000

 45629000

 0.50

 0

 10

 45737000

 109770000

 0.49

0

 16

 344540000

 808860000

 0.48

 0

 299

 1.295E+10

 2.924E+10

 0.47

 0

 6

 21391000

 41855000

 0.47

Complement

 component

 1 Q Heterogeneous

 nuclear Serine/threonine-protein

Mesencephalic

Shwachman-Bodian-Diamond

TBC1 domain family member 13

 syndrome isoform 1

astrocyte-derived

neurotrophic

 factor

 kinase mTOR

ribonucleoprotein

 Q

subcomponent-binding

 protein,

mitochondrial

 C1QBP SYNCRIP

MTOR

MANF

SMU1 TBC1D13

 0

 4

 20484000

 74249000

 0.47

0

 60

 321320000

 679840000

 0.47

 0

 38

 604460000

 1.613E+09

 0.47

 0

 14

 52206000

 144780000

 0.47

 0

 121

 3.657E+09

 8.092E+09

 0.47

 0

 109

 3.184E+09

 7.587E+09

 0.47

Conserved oligomeric Golgi complex subunit 5

Cleavage stimulation

 factor subunit 2

Calcium-binding

U4/U6 small nuclear Prostaglandin

RalBP1-associated

 Eps

Proteasome

 subunit alpha type-5

Ketosamine-3-kinase

RNA-binding

 protein 14

domain-containing

 protein 1

 E synthase 3

 protein 39

ribonucleoprotein

 Prp4

**Protein names**

Histone-binding

 protein RBBP7

Tripeptidyl-peptidase

 2

**Gene names**

RBBP7

TPP2 COG5 CSTF2

CAB39

PRPF4

PTGES3

REPS1

PSMA5

FN3KRP

RBM14

 0

 83

 606470000

 1.446E+09

 0.46

 0

 7

 16246000

 54477000

 0.46

 0

 107

 1.677E+09

 4.011E+09

 0.46

 0

 8

 13894000

 28102000

 0.46

 0

 110

 2.02E+09

 5.058E+09

 0.46

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

 0

 42

 168190000

 621480000

 0.46

 0

 24

 198430000

 418650000

 0.46

 0

 39

 128240000

 239460000

 0.46

0

 5

 14333000

 32372000

 0.46

0

 173

 523060000

 1.368E+09

 0.45

 0

 160

 2.134E+09

 4.792E+09

 0.45

 **Q-value**

 **Score**


**Protein IDs**

**229**

P52815 A0A024R1I3 A0A2R8YDS2

J3KQA0 Q5W0C6

B4DSK7

Q99549

**Table 2.** *The proteins of 116* 

*ivermectin.*

 *Reproduced*

 *from Li et al. [4], with copyright permission*

*EIF4A3-biding*

 *mRNAs and EIF4A3 were inhibited by ivermectin,*

 *identified with SILAC quantitative*

 *copyright 2020.*

 *from nature springer publisher,*

 *proteomics*

 *in ovarian cancer cells treated with (H) and without (L)*

Mediator of RNA polymerase

 II

> M-phase

> phosphoprotein

 8

transcription

 subunit 1

39S ribosomal protein L12,

Pyridoxal phosphate phosphatase

Ras/Rap

GTPase-activating

 protein SynGAP

Synaptotagmin-1

Torsin-3A

mitochondrial

**Protein names**

**Gene names**

MRPL12

PDXP SYNGAP1

SYT1 TOR3A

MED1

MPHOSPH8

 0

 12

0

 15782000

 NaN

*The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer*

 0

 2

0

 14356000

 NaN

 0

 3

0

 16493000

 NaN

*DOI: http://dx.doi.org/10.5772/intechopen.95556*

0

 26

0

 339450000

 NaN

 0

 2

0

 18400000

 NaN

0

 6

0

 40714000

 NaN

 0.01

 2

0

0

NaN

 **Q-value**

 **Score**


### **Table 2.**

*The proteins of 116 EIF4A3-biding mRNAs and EIF4A3 were inhibited by ivermectin, identified with SILAC quantitative proteomics in ovarian cancer cells treated with (H) and without (L) ivermectin. Reproduced from Li et al. [4], with copyright permission from nature springer publisher, copyright 2020.*
