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

**Protein IDs**

**228**

Q9NPD3 Q9UHB9

F5H0P4 Q96SB4 Q9Y6W5 A0A024R8S5 A0A2X0SF71

P09496 R4GMU1 Q8NCN5 Q8WY22

Q6IB29 O15031 C9JYQ9 Q9UNS2 A0A0G2JNZ5 A0A140VK17

F5GWG3

S4R3V8 Q9NWT6

B7ZBQ1 H3BR38

Mediator of RNA polymerase

Target of rapamycin complex subunit LST8

Pyruvate

dehydrogenase

 phosphatase

 regulatory subunit,

BRI3-binding

Probable

rRNA-processing

Plexin-B2 60S ribosomal protein L22-like 1

COP9 signalosome

 complex subunit 3

Glucosylceramidase

EH Retinoic Lipolysis-stimulated

Hypoxia-inducible

 factor 1-alpha inhibitor

 II

transcription

 subunit 20

 lipoprotein

 receptor

acid-induced

 protein 3

domain-binding

 protein 1

 protein EBP2

 protein

mitochondrial

 PDPR BRI3BP

EBNA1BP2

PLXNB2

RPL22L1

COPS3

GBA EHBP1

GPRC5A

LSR HIF1AN

MED20

MLST8

 0

 3

0

 13473000

 NaN

 0.01

 2

0

 18220000

 NaN

 0

 17

0

 46940000

 NaN

0

 4

 26182000

 34332000

 1.05

 0

 11

 149190000

 185790000

 0.76

 0

 4

 6547700

 17018000

 0.71

0

 6

 118570000

 187510000

 0.67

 0

 56

 157900000

 294180000

 0.66

 0

 6

 616860000

 1.011E+09

 0.66

 0

 18

 30986000

 221240000

 0.62

 0

 6

 30468000

 61825000

 0.62

 0.01

 2

 5099700

 6146700

 0.62

**Protein names**

Exosome complex component

Signal recognition

 particle subunit SRP68

Porphobilinogen

SRSF protein kinase 1

Wiskott-Aldrich

 syndrome protein family member 2

Protein

Rho

GTPase-activating

Clathrin light chain A

GDH/6PGL

endoplasmic

 bifunctional

 protein

 protein 17

disulfide-isomerase

 deaminase

 RRP41

**Gene names**

EXOSC4

SRP68

HMBS

SRPK1

WASF2

P4HB ARHGAP17

CLTA H6PD

 0 0

 3

 10312000

 28116000

 0.60

 4

 20789000

 34525000

 0.60

0

 7

 508650000

 765700000

 0.58

 0

 28

 59467000

 116590000

 0.58

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

0

 300

 1.656E+10

 2.799E+10

 0.57

 0

 22

 69082000

 151250000

 0.57

 0

 49

 123510000

 199050000

 0.57

 0

 9

 38322000

 129490000

 0.57

 0

 68

 343910000

 687640000

 0.57

 0

 25

 239980000

 490570000

 0.57

 **Q-value**

 **Score**

and promoted cell apoptosis of human ovarian cancer cells. Drug pathway network analysis of ivermectin revealed that it was significantly related to the key molecules of four energy metabolism pathways, and RT-qPCR and immunoaffinity blot analyses found that ivermectin significantly regulated these key molecules for those energy metabolism pathways, including PFKP in glycolysis, IDH2 and IDH3B in Kreb's cycle, ND2, ND5, CYTB, and UQCRH in oxidative phosphorylation, and MCT1 and MCT4 in lactate shuttle. The integrative analysis of TCGA transcriptomics and mitochondrial proteomics in ovarian cancer revealed that 16 survival-related lncRNAs were mediated by ivermectin, which were further confirmed with RT-qPRC in human ovarian cancer cells. SILAC quantitative proteomics analysis revealed that the expressions of RNA-binding protein EIF4A3 and 116 EIF4A3-interacted genes were extensively inhibited by ivermectin. Those 116 EIF4A3-interacted proteins included those key molecules in four energy metabolism pathways, and those lncRNAs regulated EIF4A3-mRNA axes. Thus, ivermectin mediated lncRNA-EIF4A3-mRNA axes in ovarian cancer to exert its anticancer activities. Moreover, lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565), which was significantly associated with overall survival and clinicopathologic characteristics of ovarian cancer patients. These ivermectinrelated molecular pattern alterations benefit for prognostic assessment and personal-

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

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

ized drug therapy in the context of 3P medicine practice in ovarian cancer.

clinical experiments for its real application in ovarian cancers.

**Acknowledgements**

2014AA020610-1 to XZ).

**Conflict of interest**

people or organizations.

**Author's contributions**

**Acronyms and abbreviations**

FDA Federal Drug Administration

RT-qPCR quantitative real-time PCR

TCGA The Cancer Genome Atlas

**231**

mtDEPs differentially mitochondrial proteins

SILAC stable isotope labeling with amino acids in cell culture

Moreover, one must realize that these achieved data about the anti-cancer activities of ivermectin in ovarian cancers are derived from the *in vitro* cell models. It is necessary to expand it into the *in vivo* animal experiments and pre-clinical and

The authors acknowledge the financial supports from the Shandong First Medical University Talent Introduction Funds (to X.Z.), the Hunan Provincial Hundred Talent Plan (to X.Z.), and the grants from China "863" Plan Project (Grant No.

We declare that we have no financial and personal relationships with other

X.Z. conceived the concept, designed the manuscript, wrote and critically revised the manuscript, coordinated and was responsible for the correspondence work and financial support. N.L. participated in preparing figures, and partial literature analysis.

### **Figure 7.**

*RT-qPCR analysis revealed the effects of ivermectin on lncRNAs in ovarian cancers relative to control cells. Reproduced from Li et al. [4], with copyright permission from nature springer publisher, copyright 2020.*

### **Figure 8.**

*Lasso regression identified and optimized the prognostic model of ivermectin-related three-lncRNA signature in ovarian cancers. (A and B). Lasso regression complexity is controlled by lambda using the glmnet R package. (C). Overall survival analysis of three-lncRNA signature between high-risk and low-risk groups. Reproduced from Li et al. [4], with copyright permission from nature springer publisher, copyright 2020.*

### **4. Conclusions**

Ivermectin, as an old, common, and classic anti-parasite drug, has demonstrated its effective *in vitro* anti-cancer efficiency for ovarian cancer. Ivermectin significantly inhibited cell proliferation, growth and migration, blocked cell cycle progression,

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

and promoted cell apoptosis of human ovarian cancer cells. Drug pathway network analysis of ivermectin revealed that it was significantly related to the key molecules of four energy metabolism pathways, and RT-qPCR and immunoaffinity blot analyses found that ivermectin significantly regulated these key molecules for those energy metabolism pathways, including PFKP in glycolysis, IDH2 and IDH3B in Kreb's cycle, ND2, ND5, CYTB, and UQCRH in oxidative phosphorylation, and MCT1 and MCT4 in lactate shuttle. The integrative analysis of TCGA transcriptomics and mitochondrial proteomics in ovarian cancer revealed that 16 survival-related lncRNAs were mediated by ivermectin, which were further confirmed with RT-qPRC in human ovarian cancer cells. SILAC quantitative proteomics analysis revealed that the expressions of RNA-binding protein EIF4A3 and 116 EIF4A3-interacted genes were extensively inhibited by ivermectin. Those 116 EIF4A3-interacted proteins included those key molecules in four energy metabolism pathways, and those lncRNAs regulated EIF4A3-mRNA axes. Thus, ivermectin mediated lncRNA-EIF4A3-mRNA axes in ovarian cancer to exert its anticancer activities. Moreover, lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565), which was significantly associated with overall survival and clinicopathologic characteristics of ovarian cancer patients. These ivermectinrelated molecular pattern alterations benefit for prognostic assessment and personalized drug therapy in the context of 3P medicine practice in ovarian cancer.

Moreover, one must realize that these achieved data about the anti-cancer activities of ivermectin in ovarian cancers are derived from the *in vitro* cell models. It is necessary to expand it into the *in vivo* animal experiments and pre-clinical and clinical experiments for its real application in ovarian cancers.
