Cancer Letters

Cancer Letters

Volume 187, Issues 1–2, 10 December 2002, Pages 121-127
Cancer Letters

Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells

https://doi.org/10.1016/S0304-3835(02)00360-9Get rights and content

Abstract

Morphine is frequently used for cancer patient's terminal medical care to relieve cancer pain. In the present study, we examined the inhibitory effect of morphine on experimental lung metastasis and invasion of colon 26-L5 cells. Morphine was found to significantly reduce the number of tumor colonies and the weight of the tumor-containing lung. Morphine inhibited the adhesion and migration of colon 26-L5 cells to extracellular matrix components and invasion into reconstituted basement membrane Matrigel, without affecting the cell proliferation in vitro. Notably, naloxone, an antagonist of morphine, abrogated morphine-induced inhibition of tumor cell adhesion, but did not affect the inhibitory effect on the production of matrix metalloproteinases (MMPs) from tumor cells. These results suggest that morphine inhibited the adhesive and invasive properties of tumor cells by different inhibitory mechanisms that involved the mediation of an opioid receptor.

Introduction

In cancer patients, morphine is mainly used to relieve pain in order to improve the quality of life. The pain of patients with cancer includes pain caused directly by tumor tissues [1] or related indirectly to the treatment of cancer, such as surgery, chemotherapy, and radiotherapy [2], [3]. Many studies have reported that physiological, psychosocial and painful stress enhances tumor growth, progression and metastasis, partly by suppressing immune responses of the host [4], [5], [6], [7], [8]. In contrast, morphine has been shown to decrease tumor metastasis through removing the painful and surgical stress [9], [10]. However, there have also been conflicting reports that morphine promoted tumor growth and reduced the survival rate of tumor-bearing animals, possibly due to immunosuppression [11]. Several studies have indicated that morphine seems to possess direct anti-tumor effects including the inhibition of tumor growth [12] and angiogenesis [13]. Therefore, it is important to determine the anti-tumor and anti-metastatic effects of morphine and the underlying mechanisms in detail.

In the present study, we focused on examining the anti-metastatic effect of analgesic doses of morphine in vivo using the model of experimental metastasis caused by intravenous (i.v.) inoculation of a tumor, which may not induce cancer pain. We also investigated the effect of morphine on the invasion, migration and adhesion of tumor cells, which are considered to be crucial steps in the sequential process of tumor metastasis.

Section snippets

Chemicals

Morphine hydrochloride and naloxone hydrochloride were purchased from Sankyo Co. Ltd (Tokyo, Japan) and Wako Pure Chemicals (Osaka, Japan), respectively.

Animals

Six-week-old male BALB/c mice were obtained from Japan SLC Inc., Hamamatsu. They were randomly assigned to be group-housed in an animal laboratory which was maintained at constant temperature (22±2 °C) and relative humidity (55±10%) and with a 12-h light/dark cycle. Food and water were freely available. This study was conducted in accordance

Effect of morphine on experimental lung metastasis of colon 26-L5 cells

We investigated the effect of morphine on experimental lung metastasis produced by i.v. injection of colon 26-L5 cells. Mice were administered morphine i.p. at the analgesic dose of 10 mg/kg six times after i.v. inoculation of tumor cells. Fig. 1 shows that administration of morphine resulted in a significant reduction of the number of tumor colonies in the lung and the weight of the lung as compared with those in the untreated control.

Effect of morphine on the invasion, adhesion and migration of colon 26-L5 cells.

We first investigated the effect of morphine on the invasion

Discussion

The present study demonstrated that administration of an analgesic dose of morphine attenuated experimental lung metastasis produced by i.v. inoculation of colon 26-L5 cells, possibly through inhibition of the adhesion to, and invasion and migration through and enzymatic degradation of the ECM. There have been some previous reports showing that the administration of morphine inhibited the growth and metastasis of tumors in vivo [9], [10]. Since painful stress, including the pain of cancer and

Acknowledgements

This work was supported in part by a grant-in-aid for cancer research (no. 12217050) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. We thank Ms K. Hayashi for her technical assistance.

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