Antitumoral Action of the Neurokinin-1-Receptor Antagonist L-733,060 and Mitogenic Action of Substance P on Human Retinoblastoma Cell Lines

Muñoz, Miguel; Rosso, Marisa; Pérez, Ana E.; Coveñas, Rafael; Rosso, Rosario; Zamarriego, Carmen; Soult, Juan A.; Montero, Ignacio

doi:10.1167/iovs.04-1530

Cited by 53 publications

(62 citation statements)

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“…This is in agreement with previous studies, in which the use of SP peptide antagonists other than L-733,060 inhibited, both in vitro and in vivo, the growth of small cell lung cancer [18] , and it is also known that the nonpeptide antagonist L-732,138 exerts antitumor action on a glioma cell line [29] . Finally, our observations are in agreement with recent findings showing that L-733,060 has antitumor activity against other human cancer cell lines such as neuroblastoma, glioma, melanoma, retinoblastoma and pancreas adenocarcinoma [9,11,12,20] . It should be noted that in cell lines as different as those mentioned above, as well as in gastric and colon adenocarcinoma, the same NK-1 receptor antagonist (L-733,060) elicits growth inhibition.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, in vitro and in vivo studies have demonstrated that SP antagonists inhibit the growth of both small cell lung cancer and glioma [18,19] . Recently, we have also demonstrated that L-733,060 shows antitumor activity against human neuroblastoma, glioma, melanoma, retinoblastoma and pancreas carcinoma cell lines [10][11][12]20] . However, to our knowledge no study has been carried out on the antitumor effect of the potent and long-acting NK-1 receptor antagonist L-733,060 against human gastric 23132/87 and colon adenocarcinoma SW-403 cell lines.…”

Section: Introductionmentioning

confidence: 95%

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The NK-1 Receptor Is Expressed in Human Primary Gastric and Colon Adenocarcinomas and Is Involved in the Antitumor Action of L-733,060 and the Mitogenic Action of Substance P on Human Gastrointestinal Cancer Cell Lines

Rosso¹,

Robles‐Frías²,

Coveñas³

et al. 2008

Tumor Biol

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Background/Aims: It has been demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonist L-733,060 induces cell proliferation and inhibition, respectively, in several human cancer cell lines. At present, it is unknown whether such actions are exerted on human gastric and colon adenocarcinomas. We carried out an in vitro study of the growth-inhibitory capacity of L-733,060 against human gastric and colon adenocarcinomas. Methods: A coulter counter was used to determine viable cell numbers followed by application of the tetrazolium compound MTS. Immunoblot analysis was used to determine the NK-1 receptors and the DAPI method was applied to demonstrate apoptosis. Immunohistochemistry was used to demonstrate NK-1 receptors in primary human gastric and colon adenocarcinomas. Results: We observed the presence of several NK-1 receptor isoforms in human gastric and colon adenocarcinomas. Nanomolar concentrations of SP increased the growth of both cell lines and micromolar concentrations of L-733,060 inhibited the growth of such cell lines, with and without previous administration of SP. L-733,060 inhibited the growth of the 23132/87 and SW-403 cell lines in a dose-dependent manner. After administration of L-733,060, apoptosis was observed in both cell lines. In both human primary gastric and colon adenocarcinomas, a high density of NK-1 receptors was observed. Immunoreactivity, showing a diffuse cytoplasmic staining, was observed in the epithelial cells of normal and tumor glands and in numerous stromal elements. Conclusions: We demonstrated that NK-1 receptors were expressed in 23132/37 and SW-403 cell lines and in human primary gastric and colon adenocarcinomas, that SP is a mitogen and that the antitumor action of L-733,060 on both human cell lines occurs through the NK-1 receptor. Data also indicate that the cell death observed is produced by apoptosis. These data suggest that the NK-1 receptor is a new and promising target in the treatment of human gastrointestinal adenocarcinomas.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 95%

The NK-1 Receptor Is Expressed in Human Primary Gastric and Colon Adenocarcinomas and Is Involved in the Antitumor Action of L-733,060 and the Mitogenic Action of Substance P on Human Gastrointestinal Cancer Cell Lines

Rosso¹,

Robles‐Frías²,

Coveñas³

et al. 2008

Tumor Biol

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“…SP, an undecapeptide of the tachykinin peptide family, regulates multiple biological functions by binding to the NK-1 receptor (NK-1R), including cardiovascular and respiratory mechanisms, sensory perception, and response to stress, among others (7)(8)(9)(10). However, one of its most important functions is related to its action as a potent mitogen on some precancerous epithelial lesions and some human cancer cell lines, e.g., glioma, retinoblastoma, neuroblastoma, melanoma, and laryngeal carcinoma as previously reported by our group (6,(11)(12)(13)(14)(15)(16)(17). These observations suggest that SP may play a role in cancer development by acting as a promoter of cell growth.…”

Section: Introductionmentioning

confidence: 86%

Substance P and NK-1R expression in oral precancerous epithelium

González‐Moles

Brener²,

Ruiz‐Ávila³

et al. 2009

Oncol Rep

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Abstract. The objectives of this study were to investigate the presence and distribution of substance P and neurokinin 1 receptor in oral premalignant epithelium and their relation with the presence of dysplasia, and to analyze whether the expression of substance P can be considered an early oncogenic event in oral carcinogenesis. Substance P and neurokinin 1 receptor expression was immunohistochemically studied in 83 oral carcinomas and adjacent nontumor epithelia. The presence and degree of epithelial dysplasia was assessed according to WHO criteria. The nuclear, cytoplasmic, and membrane expression of substance P and the cytoplasmic and membrane expression of neurokinin 1 receptor were assessed in tumor and adjacent non-tumor epithelium. Nuclear and cytoplasmic expression of substance P in non-tumor epithelium was significantly associated with the presence of epithelial dysplasia (p<0.001) and carcinoma in situ (p=0.021). Nuclear, cytoplasmic, and membrane expressions of substance P in non-tumor epithelium were significantly (p<0.001) associated with its expression in the corresponding tumor. These findings suggest that substance P plays a role in early oral carcinogenesis by promoting the proliferation and growth of premalignant fields. IntroductionThe development of oral carcinoma is a multistep process involving multiple oncogenic alterations (1). Some of these are considered early oncogenic events, including changes in chromosomal regions 3p, 9p, and 17p (2,3). Although tumor suppressor genes and putative oncogenes in these regions have yet to be identified (4), these chromosomal areas are known to be carriers of important cell-cycle and apoptosis-regulating genes. Thus, CDKN2A locus, which encodes for p16 protein, is located in chromosome 9p21, and p53 gene is in chromosome 17p13 (5). These early oncogenic events have been demonstrated in precancerous fields (4) and endow cells with an increased proliferation rate that affords them a growth advantage over epithelial cells of the adjacent healthy oral mucosa. This phenomenon considerably increases the number of target cells in which new oncogenic events can take place, which would ultimately lead to the development of one or more invasive carcinomas (4).There has been increasing interest over the past few years in the role of substance P (SP) in the development and progression of certain types of tumor (6). SP, an undecapeptide of the tachykinin peptide family, regulates multiple biological functions by binding to the NK-1 receptor (NK-1R), including cardiovascular and respiratory mechanisms, sensory perception, and response to stress, among others (7-10). However, one of its most important functions is related to its action as a potent mitogen on some precancerous epithelial lesions and some human cancer cell lines, e.g., glioma, retinoblastoma, neuroblastoma, melanoma, and laryngeal carcinoma as previously reported by our group (6,(11)(12)(13)(14)(15)(16)(17). These observations suggest that SP may play a role in cancer development by acting as a promot...

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“…Studies indicate, however, that the effect of SP is dependent on the tumor model in which it is examined. While, in some models, SP has been found to stimulate tumor growth, other studies have documented the opposite effect (6)(7)(8)(9)(10)(11)(12)(13)(14)(28)(29)(30)(31). For example, it has been demonstrated that pre-treatment of mice with SP protects against melanoma growth by inducing anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth

Erin¹

2009

Mol Med Rep

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Abstract. Substance P, a member of the tachykinin family, is expressed in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical naevi, and spindle and epithelioid cell naevi. The role of substance P in cancer development and progression is not clear. Radiotherapy, which is used extensively in the treatment of malignancies, alters substance P levels. It is, however, not known whether radiotherapy affects substance P levels in melanomas or in the tumor microenvironment. Given the fact that melanomas express substance P, possible radiation-induced changes in substance P content may underlie their radio-resistance. Hence, the aim of the present study was to determine the effects of radiotherapy on the growth of B16F10 melanomas as well as on the tumor and systemic expression of substance P. In vivo exposure of tumor-bearing C5BL/6 mice to ionizing radiation (45 Gy administered in three fractions) arrested tumor growth for three weeks and induced 3-fold increases in survival, as well as decreasing substance P levels in primary tumors and the surrounding skin. Although radiotherapy was applied locally (1 x 1 cm) at the mid-flank region of the animal, it also induced systemic changes in the levels of substance P. Specifically, radiotherapy decreased substance P levels in skin distant from the radiation field as well as in the lungs and adrenals. In order to understand the significance of this effect, B16F10 cells and cells made from metastatic lesions (B16LNAD cells) were treated with substance P. Substance P inhibited the growth of B16F10 and B16LNAD cells and further potentiated the inhibitory effects of radiotherapy. These findings demonstrate for the first time that substance P inhibits melanoma growth, and that radiotherapy-induced decreases in substance P levels may underlie the radio-resistance of melanomas.

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Antitumoral Action of the Neurokinin-1-Receptor Antagonist L-733,060 and Mitogenic Action of Substance P on Human Retinoblastoma Cell Lines

Abstract: The findings demonstrate that substance P is a mitogen and also indicate that the neurokinin-1 receptor antagonist L-733,060 acts on both human retinoblastoma cell lines as an antitumoral agent.

Cited by 53 publications

References 23 publications

The NK-1 Receptor Is Expressed in Human Primary Gastric and Colon Adenocarcinomas and Is Involved in the Antitumor Action of L-733,060 and the Mitogenic Action of Substance P on Human Gastrointestinal Cancer Cell Lines

The NK-1 Receptor Is Expressed in Human Primary Gastric and Colon Adenocarcinomas and Is Involved in the Antitumor Action of L-733,060 and the Mitogenic Action of Substance P on Human Gastrointestinal Cancer Cell Lines

Substance P and NK-1R expression in oral precancerous epithelium

Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth

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