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Mediators Inflamm
2016 Jan 01;2016:2457532. doi: 10.1155/2016/2457532.
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Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A₄.
Brigatte P
,
Faiad OJ
,
Ferreira Nocelli RC
,
Landgraf RG
,
Palma MS
,
Cury Y
,
Curi R
,
Sampaio SC
.
Abstract
We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs.
Figure 3. Effect of CTX on plasma levels of LXA4 and 15-epi-LXA4 in Walker 256 tumor-bearing rats. Not tumor-bearing (NT) or Walker 256 tumor-bearing rats were s.c. daily treated with saline (vehicle control) or CTX (18 µg per rat), during 5 days (first injection on day 1, immediately after tumor cell inoculation or same volume of saline). Rats were also treated with Boc-2 (5 μg per rat /1 mL, i.p.) or same volume of saline, daily, during 5 days, 30 minutes before the s.c. injection of CTX or saline. On the fifth day of treatments, the animals were anesthetized for the collection of blood and plasma was obtained to determine (a) LXA4 or (b) 15-epi-LXA4 levels. Each point represents the mean ± SEM of 5 rats. ∗
p < 0.05, significantly different from mean values for saline injected rats after cell injection. ∗∗
p < 0.05, significantly different from mean values for the Boc-2 + CTX group.
Figure 4. Effects of CTX and LXA4 on tumor growth. Not tumor-bearing (NT) or Walker 256 tumor-bearing rats were s.c. daily treated with saline (vehicle control) or CTX (18 µg per rat) or LXA4 (2.5 µg per rat/1 mL), during 5 days (first injection on day 1, immediately after tumor cell inoculation or same volume of saline). Rats were also treated with Boc-2 (5 μg per rat/1 mL, i.p.) or the same volume of saline, daily, during 5 days, 30 minutes before the s.c. injection of CTX or saline. On day 5 of treatments, tumor growth was performed with aid of a micrometer, by volume increase (edema) of paws up to the tibiotarsal articulation. Each point represents the mean ± SEM of 5 rats. ∗
p < 0.05, significantly different from mean values for normal NT animals. ∗∗
p < 0.05, significantly different from mean values for rats injected with saline or Boc-2.
Figure 5. Effects of CTX and LXA4 on formation and diameters of blood vessels. NT animals or Walker 256 tumor-bearing rats were s.c. daily treated with saline (vehicle control) or CTX (18 µg per rat) or LXA4 (2.5 µg per rat/1 mL), during 5 days (first injection on day 1, immediately after tumor cell inoculation or same volume of saline). Rats were also treated with Boc-2 (5 μg per rat/1 mL, i.p.) or the same volume of saline (control), daily, during 5 days, 30 minutes before the s.c. injection of CTX or saline. On the fifth day of treatments, the animals were euthanized to obtain the paws for histological analysis and determination of the (a) number of vessels and (b) vessel diameters. In (c), NT animal (1) and Walker 256 tumor-bearing rats treated with saline (2); CTX (3); LXA4 (4); Boc-2 + saline (5); Boc-2 + CTX (6); and Boc-2 + LXA4 (7, 8). (∗) Number of the vessels. The slides (E), (D), and (H) show epidermis, dermis, and hypodermis, respectively. Each point represents the mean ± SEM of 5 rats. ∗
p < 0.05 significantly different from mean values for NT rats. ∗∗
p < 0.05, significantly different from mean values for saline injected rats. #
p < 0.05, significantly different from mean values for Boc-2 treated rats.
Figure 6. Proposed scheme for CTX action on Walker 256 tumor growth suppression. Subcutaneous injection of Walker 256 carcinoma cells in the plantar region of the rat right hind paw promoted a marked infiltration of leukocytes into the deep dermis that migrated from the systemic circulation. Five days after tumor cell injection, there was a marked proliferation of tumor cells. Monocyte chemotactic factors or extracellular matrix proteins are secreted by solid tumor, which attract and activate macrophages. Animals treated with CTX showed increased plasma levels of LXA4 and its analogue being probably released by leukocytes (mainly macrophages but also neutrophils and monocytes). The increased formation of LXA4 and 15-epi-LXA4 is accompanied by tumor growth reduction and a significant decrease in both number and diameter of vessels and therefore pain attenuation. CTX actions require the participation of FPRs.
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