MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Dohledat

L-arginine a L-cystein ?

  • Dohledat

DIRAS3 (ARHI)

Artemisinin derivatives

  • Inhibit epithelial ovarian cancer cells via autophagy-mediated cell cycle arrest
  • The antimalaria compound and its derivatives
    • Artesunate (ART)
    • Dihydroartemisinin (DHA)
  • Proven to be potent anticancer drugs through various anticancer mechanisms

ART and DHA on SKOV3 and primary EOC cell growth via CCK-8 assay

  • ART and DHA
    • Inhibited EOC cell growth
    • Caused G2/M cell cycle arrest
    • Induced autophagy in EOC cells
      • Autophagy inhibitors reversed the cell growth inhibition and cell cycle arrest induced by ART and DHA
    • Suppressed the cell cycle-related NF-kappaB-signaling pathway in EOC cells
  • Artemisinin derivatives induce autophagy
  • academic.oup.com/abbs/article/50/12/1227/5158249

Stimulace BCAM, HSPA1A, and DKK1

CAR T-cell therapy

  • Patient's T cells are modified to attack cancer cells
  • Treat leukemia and other blood cancers
  • Being studied in the treatment of other types of cancer
  • New CAR T-cell engineering technique based on a two-step identification process of HER2-positive cells
    • Design a two-stage circuit that allows T cells to sharply discriminate between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2
      • Both in vitro and in vivo.
  • Key to their approach was the separation of the task of detecting HER2 from the task of killing cancer cell
  • Detection task is done by a synthetic notch (synNotch) receptor
    • Filter that constrains transcription induction to occur only when the T cell encounters target cells with extremely high expression of HER2 (i.e., cancer cells)
  • Solution requires the preliminary identification of the surface structures associated with the cancer
  • The CAR construct is adjusted to require a binding affinity that is different from the affinity used by CAR to direct the killing of these cells
  • Circuit was able to reliably discriminate between cells with an HER2 pathology score of 3+ versus those with an HER2 score of 0 or 1+ (considered "HER2-negative").
  • www.scienceboard.net/index.aspx?sec=sup&sub=cell&pag=dis&ItemID=2356

Epithelial CD8+ TILs

CFTR

  • Tumor-suppressing role in prostate cancer development (Xie et al. 2013)
  • Downregulated in breast cancer
    • Associated with poor prognosis (Zhang et al. 2013)
  • CFTR expression is significantly higher in ovarian cancer
    • Than in benign ovarian tumors and normal ovaries
    • Correlates with cancer progression and aggressiveness (Xu et al. 2015)
  • CFTR knockdown
    • Suppresses the malignant behavior of ovarian tumor cells
      • Cell invasion, motility and proliferation
  • CFTR as a novel tumor marker for ovarian cancer
    • Particularly for aggressive carcinoma
  • May have important implications for RAI treatment in NIS-expressing tumors
    • Downregulation of CFTR would improve radioiodide retention
      • Therefore more efficient effects
  • erc.bioscientifica.com/view/journals/erc/25/4/ERC-17-0515.xml

DIRAS3-derived peptide se vyvíjí

Hesperidin

  • Vitamin P flavonoid compound
  • Primarily present in citrus fruits

A2780 cells

  • Hesperidin for 6, 12 or 24 h
  • Hesperidin decreased the viability of A2780 cells
    • Increased cytotoxicity in a dose- and time-dependent manner
  • Hesperidin induced apoptosis
  • Increased cleaved caspase-3 protein expression levels in A2780 cells
  • Hesperidin markedly increased the protein expression of
    • Anti-growth arrest- and DNA damage-inducible gene 153
    • Anti-CCAAT'enhancer-binding protein homologous protein
    • Glucose-regulated protein 78
    • Cytochrome c in A2780 cells
  • Hesperidin inhibits cell viability and induces apoptosis in ovarian cancer cells
    • Via endoplasmic reticulum stress signaling pathways
  • Hesperidin may offer a novel therapeutic tool for ovarian carcinoma.
  • pubmed.ncbi.nlm.nih.gov/29142606/
  • Hesperidin: Typical doses range from 10 mg to 100 mg.
  • pinestreetfoundation.org/ovarian-cancer-chemotherapy-antioxidants/

Rutin

IL-2 + pembrolizumab (Keytruda)

Mice with mesothelioma- Genetically engineered cells to produce the cytokine interleukin-2 (IL-2)

  • Loaded them onto alginate beads to create a 1.5 mm-wide implant
  • Seven mice of 7 that received the implant + anti-programmed cell death 1 (anti-PD-1) checkpoint therapy
    • Had a complete response without recurrence.
  • Source of IL-2 next to the tumor
    • Without exposing patients to onerous dosing regimens and toxicities such as vascular leak syndrome.
  • + high dose of immunotherapy to the pleural space
    • Without causing significant systemic exposure to the drug.
  • Implant eliminated tumors in more than half of the treated animals
  • Addition of an anti-PD-1 checkpoint inhibitor - blockbuster antibody pembrolizumab (Keytruda),
    • Increased the complete response rate to 100% in the seven mice that received the combination therapy

Clinical trial in ovarian cancer

Inhibition of RXFP1 or relaxin

  • Increased cisplatin sensitivity of OC cell lines
  • Abrogated in vivo tumor formation

Relaxin-neutralizing antibody


Bacterial lipopolysaccharide (LPS)



Lodhra [Symplocus racemosa]


Aktivace NF-kappaB

Natural Killer Cell Therapy (NKT)

PI3-K inhibitors

  • Used in cisplatin-resistant ovarian cancer cell lines
    • Exhibited reduction in CD44variant6, CD117, ALDH1A1, and Snail expression
  • cdrjournal.com/article/view/3829

Sitagliptin

  • A selective DDP4 inhibitor
  • Increases caspase 3/7 activity in OC by co-treatment with paclitaxel
  • And maintains apoptosis induction through the ERK and Akt signaling pathway
  • Application of ADA and DDP4 inhibitors
    • Seems to favor tumor-cell death
  • Addition of ADA reversed the decreased metastatic capacity of OC caused by adenosine
  • Overexpression of DDP4
    • Leads to enhanced chemosensitivity of OC cells to paclitaxel
    • Reduced tumor cell invasiveness due to aberrant expression of E-cadherin, MMP-2 and TIMP
  • ADA and DDP4 still need substantial and in-depth studies and their interaction could act as potential biomarkers or therapeutic targets in OC.
  • ovarianresearch.biomedcentral.com/articles/10.1186/s13048-022-01022-z

Tumor-infiltrating T cells

  • Associated with clinical outcomes in ovarian cancer (Zhang et al., 2003)
  • Evaluating 186 frozen tissue samples from patients with advanced ovarian cancer
    • 5-year OS rate was higher in patients whose tumors had T cell infiltration
      • Compared to survival of patients whose tumors did not have T cell infiltration
  • Intratumor T cells
    • Were significantly associated with delayed relapse (Zhang et al., 2003).

CD8+ T lymphocyte infiltration

  • Extended survival time.
  • In Hamanishi’s research patients with CD8+ T lymphocyte infiltration
    • Had prolonged PFS and OS (Hamanishi et al., 2007)
  • Sato et al. (2005) - patients with high percentages of CD8+ T cells
    • Had a greater survival rate
      • Than that of patients with low percentages (55 months vs. 26 months)
  • Clarke et al. (2009) - patients with advanced stage
    • CD8+ T lymphocyte infiltration was linked to increased PFS, OS and disease-specific survival
  • Ye et al. (2014) - CD137, a TNFR-family member
    • Expressed on both CD4+ and CD8+ T lymphocytes
    • Patients with CD137 expression had improved survival in ovarian cancer.
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

TGF-beta inhibitors

A-83-01

  • TGF-beta inhibitor
  • TGF-beta1 treatment stimulated HM-1 cell motility, invasion and adhesion
  • A-83-01 could counteract the effect of TGF-beta1
  • In mice treated with A-83-01
    • Longer survival time than that of the control group (Yamamura et al., 2012)

LY2109761

  • TGF-beta type I (TbetaRI) and type II (TbetaRII) kinase
  • Gao’s study - tumor-suppressive activity
    • Augmented ovarian cancer cell apoptosis

Cisplatin + LY2109761

  • Enhanced the lethal effect of cisplatin in normal and cisplatin-resistant ovarian cancer cells
  • In vivo cisplatin + LY2109761
    • Reduced the tumor volume in a cisplatin-resistant ovarian cancer model
    • LY2109761 increases the antitumor activity of cisplatin (Gao et al., 2015).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

TLR (Toll-like receptors) agonists

TLR-7 agonist

  • Activate NF-kappaB

852A (a TLR-7 agonist) Clinical trial on the antitumor activity of a TLR-7 agonist in relapsed ovarian, cervix and breast cancer

  • 15 patients, including 10 patients with recurrent ovarian cancer
  • All received 852A
  • Only one patient with stage IIIc serous ovarian cancer had stable disease after treatment
    • 24 doses of 852A
    • Did not continue the trial because of disease progression.
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Ayurveda

  • Kanchnar guggul
    • Cytotoxic effect that inhibits cell (antimicrobial) division
    • Reduces cell proliferation
  • Sahajana
    • Kaempferol and iso-quercetin
  • Giloy - Alongside glucosamine
    • Alkaloids are known as gilo in, giloinin, gilosteral, and berberine,
    • Giloy's properties
  • Gojala
    • Cow-urine therapy - cow-urine extract - main component in our medicine
    • Gojala mixed with ayurvedic herbs it becomes more effective
  • cowurine.com/en/ayurveda-treatment-for-ovarian-cancer

ALDH inhibitors

pan-ALDH1A family selective inhibitors

  • Preferentially target CD133+ ovarian CSCs
  • Upregulate the expression of mitochondrial uncoupling protein (UCP) 1 and 3
  • Reduce oxidative phosphorylation capacity,
    • Resulting in cell programmed necrosis (necroptosis)
  • Chemoresistant cells overexpress anti-apoptotic proteins
    • Triggering alternative cell death pathways, such as necroptosis, can lead to better therapeutic outcomes
  • Cisplatin or carboplatin + ALDH1A inhibitor
    • Significant tumor shrinkage in subcutaneous, intraperitoneal, and PDX models of ovarian cancer
  • cdrjournal.com/article/view/3829

Anti-IL-10R mAb

Anti-CD40 mAb

  • Can activate NF-kappaB
    • Through classical or non-classical pathways (Mantovani et al., 2004; Sica and Bronte, 2007; Mancino and Lawrence, 2010)
  • NF-kappaB modulates
    • Many crucial genes in macrophages
    • Many tumor-promoting genes, such as
      • VEGF, IL-6, TNF-alpha, and COX2 (Hagemann et al., 2009; Biswas and Lewis, 2010)
  • Inactivation of NF-kappaB
    • Mediates polarization of TAMs to immunosuppressive M2 macrophage
  • NF-kappaB reactivation
    • Adjusts TAMs to tumouricidal M1 macrophages (Biswas and Lewis, 2010)
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Ashoka [Saraca indica]

Aspalathus linearis

  • Contains aspalathin and aspalalinin
  • Chrysoeriol, luteolin, luteolin-7-o-glucoside, quercetin, quercetin-3-orobinoside, hyperoside, isoquercitrin and rutin
  • Xi et al., 2018 - Quercetin slowed down and possibly reversed metastasis
    • By interfering with uPA/uPAR systems, AMPK, NF-kappaß, ERK1/2, and PKC regulation
  • assets.researchsquare.com/files/rs-1943447/v1_covered.pdf?c=1660579162

All-trans retinoid acid (ATRA)

  • Inhibitor of the annexin A2-S100A10 signalling pathwa
    • New therapeutic against serous ovarian cancer.
  • Annexin A2 is increased in serous ovarian cancer
  • Essential role in ovarian cancer invasion and metastasis
  • Annexin A2 plays an important role in the plasminogen activator system regulating plasmin production

in vitro

  • ATRA treatment (1-5 uM) on annexin A2 + S100A10 expression, plasmin activation
  • Ability of ATRA to inhibit serous ovarian cancer cell survival, motility and invasion
  • Cryopreserved serous ovarian cancer tissues were cultured on gelatin sponges for 72 h with ATRA (1 µM)
  • OVCAR-3, OV-90, & OAW28
    • Significantly decreased by ATRA treatment (1-5 µM)
    • ATRA (1 µM) also significantly decreased proliferation (Ki67 positivity, p = 0.0034)
  • ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms.
  • pubmed.ncbi.nlm.nih.gov/30621740/

AXL receptor tyrosine kinase (AXL) inhibitors

Berberine

Ovarian cancer cells in ascites

  • Prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs)
    • Leading to treatment failure and disease recurrence

Suspension MCS model of ovarian cancer cells in vitro

  • MCS cells acquired drug resistance to cisplatin
  • Ovarian cancer MCS showed a proliferation-stagnant but invasive phenotype when resuspended.
  • Treated with cisplatin
    • Much higher viability
    • Fewer apoptotic cells than the adherent cells
  • Bcl-2 were upregulated in ovarian cancer ascitic cells and MCS cells

Bcl-2 knockdown

  • By siRNA or blockage by ABT-737
    • Enhanced the cisplatin-induced apoptosis
    • Reduced the 50% inhibitory concentrations of cisplatin for MCS by 58.5% and 88.2%
  • Upregulated Bcl-2 contributes to cisplatin resistance in our MCS model
  • Targeting it sensitizes the MCS to cisplatin treatment
  • Provides preliminary treatment method for ovarian cancer peritoneal metastasis

Calcium channel blocker

Verapamil + doxorubicin - Clinical trial in refractory ovarian cancer patients


Brachytherapy

  • Directs radiation from the interior of the body using tiny, radioactive pellets placed near the tumor
  • Not commonly used for ovarian cancer

Camptotheca [Camptotheca acuminate]

CRL4CUL4A/DDB1 inhibition

  • Manipulates OC cell chemoresistance
  • By regulating mitochondrial dynamics and mitophagy
  • CRL4CUL4A/DDB1 depletion
    • Enhanced mitochondrial fission
      • By upregulating AMPKalphaThr172 and MFFSer172/Ser146 phosphorylation
        • Recruited DRP1 to mitochondria
  • CRL4CUL4A/DDB1 loss
    • Stimulated mitophagy
      • Through the Parkin-PINK1 pathway
        • Degrade the dysfunctional and fragmented mitochondria
    • Inhibited OC cell proliferation
      • Inhibiting autophagy partially reversed this disruption
  • Disruption of CRL4CUL4A/DDB1 and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.
  • www.nature.com/articles/s41392-022-01253-y

Reverting the Activated CAFs Into a Quiescent State

  • Cancer-associated fibroblasts (CAFs)
    • Regulate immune cells and ECM via a series of signal molecules
    • Decrease the number of MDSCs through
      • Inhibiting CXCL12/CXCR4 signal pathway
        • Promote the differentiation of myeloid cells into DCs via stimulating IL6/STAT3 signal pathway (Gok Yavuz et al., 2019; Truffi et al., 2020)
  • CAFs inhibit T cells
    • Through increase the expression of PD-L1/2
  • CAFs activate T cells
    • Via stimulating the production of IL-6 (Barnas et al., 2010; Cho et al., 2011)
  • CAFs can active the ECM
    • Through secreting growth factors (such as VEGF) and cytokines (such as TGF-beta, IL-6 and IL-10) (Kohlhapp et al., 2015).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Lipid nanoparticles, delivering mRNA that triggers the production of the follistatin

  • protein within cancer clusters
  • Following intraperitoneal administration
    • Follistatin produced works against another protein, activin A
      • Elevated activin A is linked with aggressive ovarian cancer and its associated cachexia

Mouse model

Immune checkpoint blockade

  • Genomic and proteomic analysis of EMT signatures in multiple cancers, including ovarian cancer;
  • Set of 77 EMT-related genes
    • EMT score according to their expression signature
    • EMT score was positively correlated with
      • Expression levels of immune checkpoint genes
        • Predictive value of EMT score in treatment response of immune checkpoint blockade
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Increased membrane expression of MHC


Inhibice membrane ABC (ATP-binding cassete) transporter - P-glycoprotein (P-gp) - multidrug resistance protein 1), MDR1, ABCB1


Inhibice CD138


Inhibice CAPG, LCK and TNFAIP6


Inhibice CCNE1


Inhibice CD146


Inhibice Chloride intracellular channel protein 3 (CLIC3)


Inhibice CXCL12beta


Inhibice CXCL14


FAK inhibitor

VS-6063

Inhibice fibroblast activation protein alpha (FAPalpha)


Direct deletion FAP+ fibroblasts

  • Activated CAFs can selectively express a variety of different biomarkers
    • Alpha-SMA FAP, S100A4 and PDGFR (Barrett and Puré, 2020)
  • FAP is a serine protease
    • Regulates the recruitment, proliferation and differentiation of myofibroblasts
    • Important surface marker in CAFs
    • More than 90% of CAFs (Chen and Song, 2019)
  • Promote tumor progression
  • Block immunotherapy by producing ECM and direct signaling pathways (Puré and Blomberg, 2018).
  • Inhibition of FAP
    • Can reduce the infiltration of CAF (Santos et al., 2009)
    • Targeted therapy for FAP on CAF was proposed.
  • Patients with high FAP expression showed poor OS
  • Blocked the FAP via a FAP-specific siRNA
    • Proliferation of cells was reduced 9–13% (Mhawech-Fauceglia et al., 2015)
  • Downregulated FAP+ fibroblasts could reduce the proliferation of tumor cells
    • Might be a new treatment for ovarian cancer.
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Targeting Hedgehog, FAK and IL-6

  • Effective treatment for ovarian cancer

IPI-126

Inhibice IL-10 from CD4+ T cells



Inhibice Methyltransferase nicotinamide N-methyltransferase (NNMT)


Inhibice nitric oxide synthase (NOS)


Inhibice factor-1 (SDF-1)


Inhibice FOXP3+ regulatory T lymphocytes (Tregs)


Inhibice ADAM17


Inhibice Ang2

CCL2 inhibice

  • Also called monocyte chemotactic protein-1 [MCP-1]
  • Member of the MCP chemokine family
  • Produced by tumor cells and stromal cells such as myeloid cells, ECs and fibroblasts
  • Acts as a chemoattractant for T cells, NK cells and monocytes (Ueno et al., 2000; Conti and Rollins, 2004)
  • CCR2 is a receptor of CCL2, including CCR2A and CCR2B
  • CCA2B is the main isoform of CCR2
    • Highly expressed on NK cells and monocytes
  • CCR2A is expressed on smooth muscle cells and a portion of monocytes
  • CCL2-CCR2 signaling
    • Involved in tumor metastasis (Lim et al., 2016)
    • Initial stage of metastasis, tumor cells breakdown ECM and travel to blood vessels
    • CCL2 guides the migration of cancer cells through linking with CCR2
  • CCL2 promotes the migration of cancer cells
    • By inducing the expression of MMP2 as well as MMP9 (Tang and Tsai, 2012)
      • Cancer cells invade into blood vessels for metastatic dissemination, which requires TAMs
  • CCL2 promotes cancer cell intravasation and extravasation
    • Chemoattractant for TAMs
  • CCL2-CCR2 signaling stimulates angiogenic switching
    • Via recruiting myeloid cells
    • Suppresses immune-mediated killing by recruiting MDSCs (Huang et al., 2007; Low-Marchelli et al., 2013).
  • CCL2 was highly expressed on paclitaxel-resistant ovarian cancer cells
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Inhibice Galectin 9 a TIM3


Histone deacetylase 3 (HDAC3) or histone deacetylase 8 (HDAC8) inhibition

  • Caused cell death in ovarian cancer cell lines
    • With a similar effectiveness as generic pan-HDAC inhibition
  • HDAC3 or HDAC8 inhibition combined with Bcl-xL inhibition
    • Had a synergistic effect on the percentage of dead cells post treatment
  • HDAC3 inhibition causing cell death in all ovarian cancer cells line and a lung cancer cell line
  • HDAC8 inhibition only causing cell death in ovarian cancer cell lines.
  • dash.harvard.edu/handle/1/42004173

Inhibice Indoleamine 2,3-Dioxygenase (IDO)

  • Enzyme catalyzing tryptophan degradation
    • (Munn et al., 2005; Tanizaki et al., 2014; Munn and Mellor, 2016)

Inhibice I-L 4


Suppressing Macrophage Recruitment

Inhibice p38-MAPK pathway


STAT3 Inhibice

  • STAT3, a member of the STATs (Signal Transducers and Activators of Transcription) family
  • Can be activated by various receptors
    • IL-6 and IL-10, IL-11 , VEGF, EGF and FGF (Chai et al., 2016; Furtek et al., 2016)
      • Activation of JAKs - JAK1 and JAK2
        • Induce the phosphorylation of STAT3 at Tyr705 and lead to the translocation of activated STAT3 dimers to the nucleus
          • Binds to DNA and enhances gene transcription (Yu H. et al., 2014)
  • STAT3 could modulate tumorigenesis
    • Regulates the expression of c-Myc and cyclin D1 (Luwor et al., 2013)
    • Modulates angiogenesis via the gene expression of VEGF and IL-8
    • Regulates migration by MMP-2 and MMP-9 gene expression (Zhang et al., 2010)
    • Associated with the polarization of TAMs (Tang et al., 2013; Wang et al., 2018)
  • Inhibition of STAT3
    • Decreased TAM polarization to M2 macrophages (Fujiwara et al., 2011).

HO-3867

  • Inhibitor of STAT3
  • Significant antitumor effect on ovarian cancer (Selvendiran et al., 2010; Tierney et al., 2012; Rath et al., 2014; Tang et al., 2015; Bixel et al., 2017; Saini et al., 2017; Yoshikawa et al., 2018)
  • HO-3867 induced the apoptosis of A2780 cells
    • Through activating caspase-3 and caspase-8
    • Promoted G2/M cell-cycle arrest via regulating cell-cycle regulatory molecules such as
      • Cyclin, p21, p27, p53 and cdk2.
  • Dose-dependent reduction of tumor volume in mice with ovarian cancer
  • HO-3867 reduced tumor growth in a chemotherapy-resistant ovarian cancer model
    • Dose-dependent manner
  • HO-3867 inhibited tumor size and tumor metastasis in ovarian cancer.
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

WP1066

  • STAT3 inhibitor with antitumor activity
  • WP1066 markedly suppressed the clonogenicity and invasion activity of SKOV3 and SKOV3/DDP cells (a cisplatin-resistant ovarian cancer cell line)
  • Increased the apoptosis of SKOV3 and SKOV3/DDP cells
  • WP1066 and cisplatin in combination
    • Inhibition of proliferation and apoptosis increased compared to that of cisplatin alone
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Inhibice VEGF and VEGFR


Inhibitors of PI3-K/AKT signaling + carboplatin


CDK7 inhibition


Inhibitory metaloproteináz

  • Výhoda či nevýhoda ?

Chemoresistant cell types have an elevated dependence on OXPHOS and sensitivity to OXPHOS inhibitors

Malignant ascites

    • Hypoxic (~50% less soluble oxygen than the blood
    • Contain depleted levels of glucose

Spheroids

  • Proliferative on the surface
  • Contain a large population of quiescent cells within.
  • Can invade surface tissues, such as the omentum
    • To access more nutrients and form metastatic tumors.
  • IL-6 and IL-8 attract spheroids to the omentum
  • IL-6 may also contribute to the symptoms
    • Nausea, vomiting, and anorexia
  • In vitro multicellular tumor spheroids (MCTS)
    • Drug screens to identify compounds
  • www.mdpi.com/1422-0067/20/1/229

Ovarian cancer stem cells (CSCs)

  • Rate of proliferation similar to other tumor cells
  • Selective chemoresistance pathways and markers
  • Treating of the disease with chemotherapy, to enrich their prevalence
  • Depleted nutrients in the cellular microenvironment forces ovarian cancer cells to adapt their metabolic needs in order to survive
  • www.mdpi.com/1422-0067/20/1/229

Anti-L1 cell adhesion molecule (L1CAM) chimeric monoclonal antibody chCE7

  • For radioimmunotherapeutic (RIT) approaches to cancer
  • L1CAM is a 200–220 kDa type I membrane glycoprotein
    • Of the immunoglobulin superfamily
  • L1CAM was identified as a protein of the nervous system
    • Morphogenic events like neurite outgrowth, fasciculation, adhesion and neuronal cell migration (181)
  • L1CAM is expressed in human peripheral nerve bundles and human kidneys
  • Low levels of L1CAM are also detectable in hematopoietic cells
  • L1CAM is overexpressed in various types of human cancers
    • Ovarian and endometrial carcinoma, colon cancer, melanoma and glioblastoma
    • Usually correlates with advanced tumor stage and poor prognosis
  • L1CAM expression in cancer supports motility and invasion, promoting aggressive tumor growth and metastasis formation
  • L1CAM in combination with CD133
    • Characterized a new ovarian CSC population
  • Restricted expression of L1CAM allowed the use of anti-L1CAM mAbs for OC targeted therapies

Antibody-based L1CAM therapy in preclinical OC models

  • Internalizes by endocytosis
  • Coupled metallic radionuclides are trapped in the cell
  • Therapeutic results for RIT in solid tumors (as adjuvant therapy after primary surgery and/or chemotherapy) have been modest during recent years
  • Main obstacles include low radiosensitivity, poor lymphatic drainage
    • Limited diffusion of the antibody through tumor mass
    • Poor vascularization
    • Lack of homogeneous targeting
  • www.frontiersin.org/articles/10.3389/fonc.2020.00319/full


Macrophage Activation Therapy (MAT),

Mayapple [Podophyllum peltatum]

Morusin, Irinotecan, Rubitecan, and 10-hydroxycamptothecin

Inhibice MTHFD2

  • Noncanonical oxidative function that provides mitochondrial NAD+
  • Gene also regulates systemic metabolic activity
    • By the paralogue metabolic pathway maintained by metabolic flux compensation.

Mice study MTHFD2 inhibition

Nanothermia

Oxygenoterapie

  • Možná - dohledat

Pacific yew [TaxusBrevifolia] - Western Yew

Potlačení IL-6, IL-10


Radioterapie + další poškození DNA

  • Radioterapie je forma poškozování DNA cestou oxidačního stresu
  • Bude tedy snynergicky funovat s medikací, které blokuje DNA reparaci

Další požkození DNA

  • DNA crosslinkers,
  • Synthesis, and topoisomerase inhibitors
  • PARP inhibition
  • Blokáda antioxidační ochrany
  • Oxidační a proxidační látky
  • Inducery ferroptozy

Kmenové buňky a odolnost vůči poškození DNA

  • In response to radiation, DNA repair is initiated and controlled by the DNA damage response (DDR)
  • DDR triggers the activation of checkpoint kinase signaling pathways such as
    • Ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2)
    • ATM-Rad3-related (ATR)-checkpoint kinase (Chk1)
  • CSC populations of glioblastoma, prostate, lung, breast cancer and many others,
    • Possess high DNA repair capacity
    • Mainly due to increased activation of ATR-Chk1 and ATM-Chk2 pathways
    • Increased HR-dependent DNA repair proficiency of CSCs in OC
      • Makes them more resistant to PARP inhibition
  • OC CSCs have a high resistance to the platinum agents due to:
    • Altered regulation of cell cycle checkpoint
    • Upregulation of the Fanconi Anemia DNA repair proteins (FANCD2, FANCJ)
    • MLH1,
    • BRCA1 (134)
    • Increased expression of DNA polymerase eta

Odolnost kmenoých buněk vůči oxidačnímu stresu

  • Glutathione peroxidase
  • Superoxide dismutase
  • Catalase
  • Balance the production and the elimination of these products
  • CSCs isolated from different tumors exhibit
    • More efficient ROS scavenging systems and a lower level of ROS production
  • ALDH positive population in OC
    • Upregulation of NRF2 (Nuclear factor erythroid 2-like) signaling
  • www.frontiersin.org/articles/10.3389/fonc.2020.00319/full

Shatavari [Asparagus racemosus]

Sorbin and SH3 domain

Po chemoterapii increased NK cell infiltration and oligoclonal expansion of T cells

T-cells

Stimulace Th1 imunity


High immune activity + low mutation prevalence of foldback inversions

Increased co-stimulatory molecules (CD80, CD86, CD40)


Episode of thyroiditis

  • Spontaneous regression of cancer is extremely rare
  • Only few cases have been reported
  • Primary ovarian cancer in a 67-year-old woman
  • After an episode of thyroiditis
  • Appears to be associated with the host’s immune response, endocrine/metabolic/surgical/postoperative events, carcinogen/antigen removal, inhibition of angiogenesis, tumor necrosis, oncogene/growth factor/cytokine changes, genetic and epigenetic factors, induction of benign differentiation, apoptosis, and psychological factors.
  • link.springer.com/article/10.1007/s42399-021-00843-1

Trientine

Makrofágy M2 na M1

Triggering of MSR1 (macrophage scavenger receptor 1) in IL-4-activated macrophages

  • Leads to enhanced JNK activation
    • Promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state
  • Abolished by MSR1 deletion or JNK inhibition
  • MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients
    • May be relevant for macrophage phenotypic shift in vivo
  • Receptor's involvement in macrophage polarization
  • pubmed.ncbi.nlm.nih.gov/31028084/
  • Regulation of phagosomal maturation in so-called M1 inflammatory macrophages
  • Mechanisms facilitating phagosomal maturation in macrophages involved in tissue repair (Balce et al, 2011)
  • Th2-derived cytokines (IL-4) and (IL-13)
    • Strong anti-inflammatory macrophage phenotype = alternative-activated macrophages (M2)
  • M2 macrophages and tissue-resident macrophages - often resemble an M2-like state
    • Clear cell debris and dead cells through phagocytosis
  • M2 alternatively activated macrophages (AAMs)
    • Inhibit inflammatory responses
    • Promote angiogenesis and tissue repair
    • Synthetizing mediators required for collagen deposition
      • Important for wound healing (Gordon & Martinez, 2010)
  • IL-4 enhanced phagosomal protein degradation (Balce et al, 2011)
  • Macrophage scavenger receptor 1 (MSR1)
    • Upstream receptor that promotes the recruitment of the TAK1/MKK7/JNK signalling complex to the phagosome
  • Triggering MSR1 induces JNK activation in M2 macrophages
    • MSR1/JNK signalling pathway activation leads to a M2/M1 macrophage phenotypic switch
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC6545745/

Tyrosine kinase inhibitors

Checkpoint kinase 1 (CHK1)

Ataxia-telangiectasia and Rad3 related protein (ATR) inhibitors

WEE1 G2 checkpoint kinase (WEE1) inhibitors

  • Pivotal role in DNA damage repair response
  • Inhibitory effect on CSCs in various cancers in vitro and in vivo
  • Effect on ovarian CSCs has not been evaluated
  • cdrjournal.com/article/view/3829

7-Monohydroxyethylrutoside (MONOHER) - Venoruton

  • Flavonoid is monoHER
  • In flavonoid products, such as Venoruton
  • Derivative of the flavonoid rutin, obtained from many sources
    • Buckwheat
    • Buds of the Chinese herb Saphora japonica
    • Propolis.
  • Flavonoid monohydroxyethylrutoside (monoHER)
    • Prevented heart cell damage from doxorubicin by 15 fold
  • MonoHER may also protect ovarian cancer cells from being effectively treated by doxorubicin.
  • MonoHER reduced doxorubicin effectiveness in one type of ovarian cancer cell culture (A2780)
  • Did not interfere with doxorubicin treatment in another ovarian cancer cell line (OVCAR-3)
  • MonoHER used at high concentrations as demonstrated in this study
    • Has the potential to decrease the effectiveness of doxorubicin treatment
  • Lower concentrations of monoHER
    • More realistic in clinical use
    • Do not influenced the antitumor activity of doxorubicin. (Bruynzeel, Abou El Hassan et al. 2007)

Combined laboratory and animal study

Dohledat

  • Wild Yam,
  • St Mary's Thistle,
  • Elecampane,
  • Hawthorne,
  • Equisetum
  • Yarrow.
  • Maritime Pine Bark
    • A super antioxidant, to dramatically stimulate the patients immunity and ability to fight the cancer
O úroveň výše

Poslední aktualizace: 10. 12. 2023 21:48:29