В.A.Рихтер Пептид молока человека – лактаптин, как потенциальный противораковый препарат Москва, 2013.

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В.A.Рихтер Пептид молока человека – лактаптин, как потенциальный противораковый препарат Москва, 2013

Lactaptin purification from human milk In vivo study (clinical trial) disadvantages APOPTIN Multiple myeloma TRAIL-based proteins (anti-TRAIL-receptor mAb and recombinant TRAIL) Mapatumumab: non-Hodgkin’s lymphoma, colorectal, ovarian, prostate cancer; Lexatumumab: advanced solid tumors. Narrow range of constitutively TRAIL-sensitive tumors ER-specific mAb Herceptin- Breast cancer Rituximab- B-cell lymphoma ER-dependent spectrum of tumors MDA-7 Advanced carcinomas, melanomas Resistance of pancreatic and colorectal cancer Alfa-lactalbumin +5 molecules of oleic acid (HAMLET, BAMLET) Papillomatous skin tumor, bladded cancer, glioma Restricted spectrum of tumors (need for local administration)

Human k-casein, lactaptin and recombinant analogue RL2 GGSHHHHHH Lactaptin 8.6 kDa NH2 182 COOH 23 57 134 Human kappa-casein YYGTNLYQRRPAIAINNPYVPRTYYANPAVVRPHAQIPQRQYLPNSHPPTVVRRPNLHPSFIAIPPKKIQDKIII

RL2 cytotoxicity in vitro Cultured human cells Primary human cells

Sensitivity of mice cancer cells to RL2 Cell line IC50, μg/mL hepatoma 22 100 MX-82 hepatoma A1 (HA1) 8 L-1210 180 MX-7 170 Ehrlich carcinoma Lewis carcinoma 190

Study design Tumor cells inoculation Tumor growth RL2 therapy Control group RL2 therapy i.v. injection s.p. injection

The dose effect of RL2 on the growth rate of HA-1 tumors * ** Statistical differences in mean tumor weight between control and experimental groups are indicated by * for p < 0.01; ** for p < 0.05 (statistically significant differences between groups).

Course-dependent antitumor activity of RL2 ** * RL2 delays the formation of primary HA1 tumor

Metastasis suppression effect of RL2 control RL2 therapy P<0,001 A/Sn female mice were s.c. injected with 5x105 hepatoma HA-1 cells. RL2 (1 mg) was injected i.v. 5 times. Liver metestases

Postsurgical metastasis model A/Sn mice were i.v. injected with 2x105 hepatoma HA1 cells. Two days later RL2 (1 mg) was injected i.v. for 4 days.

RL2RL2 inhibition of MDA-MB-231 tumor growth in SCID mice

RL2 enhances antitumor effect of cyclophosphamide A/Sn female mice (5 in group) were i.p. inoculated with 2x106 hepatoma HA-1 cells. Next day mice were i.p. treated with RL2 (0.5 mg/dose) and cyclophosphamide (30 mg/kg). Therapeutic course consisted of 5 injections.

RL2 suppresses tumor growth and metastases: comparison with TNFa - Tumor cell inoculation - Repetitive RL2/TNFa injections - Tumor growth and metastases progression - Surgical removal of the tumor - Survival upon metastases response

what is the mechanism of action LACTAPTIN - induces apoptosis in cancer cells in vitro - Inhibits tumor growth in vivo what is the mechanism of action

Accumulation and distribution of RL2-Rh conjugate into MCF-7 and MSC cells Fluorescent microscopy of DAPI stained cells

Confocal microscopy of MCF-7 cells with RL2-Rh conjugate Staining DAPI (nucleus) Cell Tracker Green (cytoplasm) RL2-Rhodamin

Effect of RL2 on mitochondria membrane potential (HA1 cells) Study design Effect of RL2 on mitochondria membrane potential (HA1 cells) - control - RL2 control Cell number + RL2 JC-1 staining

Mitochondrial apoptotic pathway activation by RL2 O h 4 h 48 h A - control; B - RL2-treated cells. The apoptotic changes in MCF-7 cells after RL2 treatment (4h) were detected as a shift of Δψ Early apoptotic transition of TMP was analyzed by flow cytometry of DiOC6/PI stained MCF-7 cells

RL2 activates procaspases 8 and 9 in MCF-7 cells

Caspase 7 activity in MCF-7 cells control RL2 Western blot analysis of caspase 7 activity 1- mass marker 2- control cells 3- RL2-treated cells Population with active caspase 7

Transcriptional response of MCF-7 cells on RL2 treatment Functional groups of genes p-value Gene number Centromeric regions 1.21E-05 11 Microtubule cytoskeleton organization 3.06E-04 14 Actin cytoskeleton organization 3.83E-03 Regulation of mitotic cell cycle 1.53E-03 DNA damage response, signal transduction of p53 class mediator 9.40E-03 6 Data of НТ-12 (Illumina)-analysis

RL2 interacts with cell proteins α-and β-chains of tubulin, Identification by SwissProt database Affine chromatography of МСF-7 cells lysates electrophoresis trypsinolysis α-and β-chains of tubulin, α-actinin-1

Apoptosis pathway inducing by RL2

Work was supported by: RFBR10-04-01109-а; 11-04-12100; 13-04-01313 Our team: Olga Koval Alexandr Fomin Miraslava Potapenko Elena Kuligina Dmitry Semenov Vivarium ICG SB RAS Vasily Kaledin Valery Nikolin Histology Eugeny Nikitenko Work was supported by: RFBR10-04-01109-а; 11-04-12100; 13-04-01313 FTP № 02.740.11.0715. and 16.N08.12.1009

Expression of apoptosis-related molecules The expression levels of apoptosis-related molecules, such as Bcl-2, p53 and MDM2 in RL2-treated MDA-MB-231 cells were analyzed by Western blot. We observed that during RL2 treatment p53-cleaved protein level decreased and p53 held in active form. Active p53 able to decreases Bcl-2 protein level that can be seen in the blot. Moreover, analysis of MDM2 level in MDA-MB-231 cells shows the appearance of MDM2 cleaved form. Together, these data could indicate that RL2-dependent apoptosis in MDA-MB-231 cells was accompanied by p53 stabilization and Bcl-2 depletion.