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the mortality rate of EOC has not been significantly changed for several decades

Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer

Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations

KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3

Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC

KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition

KPNB1 functions as an antiapoptotic and proproliferative oncogene in EOC.

Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1

KPNB1 acts as an oncogene in human EOC and represents a promising therapeutic target.

ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC

ivermectin also induced apoptosis

ivermectin increased the expression levels of BAX, and cleaved PARP, as well as p21 and p27

KPNB1 inhibition is responsible for the antitumor effect of ivermectin

we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells

Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth

ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types

KPNB1 was the second-highest-ranked gene identified in our screen

Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types

our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members

higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans

none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event

we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone

metabolic activity, oxygen transport, and DNA synthesis

Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.

macrophages contain considerable quantities of iron

iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)

excess iron is retained in the liver cells

the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)

labile iron pool (LIP)

LIP is toxic to the cells owing to the production of massive amounts of ROS.

DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH

Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)

Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation

Vit-C-stimulated iron absorption

reduce cellular iron efflux

high-dose Vit-C may elevate cellular LIP concentrations

ascorbate enhanced cancer cell LIP specifically by generating H2O2

Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately

tumor cells have a need for readily available Fe(II) to survive and proliferate.

Tf has been recognized to sequester most labile Fe(II) in vivo

Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant

free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production

iron metabolism is altered in malignancies

increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways

Fe(II) ion in breast cancer cells is almost double that in normal breast tissues

macrophages in the cancer microenvironment have been revealed to increase iron shedding

Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease

increased the amount of LIP inside the cells through transferrin receptor (TfR)

Warburg effect, or metabolic reprogramming,

Warburg effect is aided by KRAS or BRAF mutations

Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts

increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)

ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring

Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production

high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis

mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2

Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.