Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma.
Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 145 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This activity mapped to the PHSRN sequence, which induced invasion through alpha5beta1 integrin. PHSCN, a competitive inhibitor, blocked both PHSRN- and serum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fold more potent; however, Ac-HSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection three times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only after surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumor growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell injection was reduced by 99.9% during the first 16 days of treatment, although subsequent tumor growth occurred. MLL tumor cryosections immunostained with anti-PECAM-1 showed that Ac-PHSCN-NH2 inhibited neovascularization by 12-fold during this time. Whether initiated after MLL cell injection or only after MLL tumor removal, Ac-PHSCN-NH2 treatment reduced the numbers of MLL lung colonies and micrometastases by 40- to >100-fold, whereas Ac-HSPNC-NH2 was inactive. Thus, Ac-PHSCN-NH2 may be a potent antitumorigenic and antimetastatic agent for postsurgical use prior to extensive metastasis.
Livant
D L
DL
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor 48109-0616, USA. dlivant@umich.edu
Brabec
R K
RK
Pienta
K J
KJ
Allen
D L
DL
Kurachi
K
K
Markwart
S
S
Upadhyaya
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001485:Basement Membrane; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D005353:Fibronectins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017469:Receptors, Fibronectin / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005353:Fibronectins; D009842:Oligopeptides; D017469:Receptors, Fibronectin; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide