The influence of mast cell mediators on migration of SW756 cervical carcinoma cells

Abstract

The role of mast cell mediators on cervical cancer cell migration was assessed using an in vitro assay of scratch wound healing onto monolayers of HPV18-positive cervical carcinoma cells (SW756). Migration of SW756 cells was accelerated by co-culture with the mast cell line LAD2. This effect was inhibited by the H1R antagonist pyrilamine and the cannabinoid agonists 2-arachidonylglycerol (2AG) and Win 55,212-2. Therefore, the specific effects of histamine and cannabinoids on SW756 migration and LAD2 activation were analyzed. Histamine added to the in vitro assay of scratch wound healing either increased or inhibited SW756 migration rate by acting either on H1R or H4R, respectively. Cannabinoids acted on CB1 receptors to inhibit SW756 migration. Supernatants from SW756 cells stimulated LAD2 cell degranulation, which in turn was inhibited by cannabinoids acting via CB2 receptors. RT-PCR showed that SW756 expressed mRNA for CB1, CB2, H1R, H2R, and H4R. On the other hand, LAD2 expressed mRNA for all four HRs and CB2. The results suggest that mast cells could be contributing to cervical cancer cell invasion and spreading by the release of histamine and cannabinoids. Therefore, therapeutic modulation of specific mast cell mediators may be beneficial for cervical cancer treatment.

Clinical Trials, Studies and Publications:

The influence of mast cell mediators on migration of SW756 cervical carcinoma cells

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

Abstract

Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.

Clinical Trials, Studies and Publications:

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

Medical Use of Marijuana by Patients Undergoing Cancer Chemotherapy or afflicted with AIDS

“Cancer chemotherapy can often prolong the patient’s life by several years. In some instances, a complete “cure” can be obtained. Unfortunately, these drugs also have severe side-effects, most notably nausea and vomiting. Patients sometimes find these effects so distressing they abandon chemotherapy entirely.

People with AIDS (Acquired Immune Disease) also experience these problems. Powerful anti-viral drugs such as AZT and the new protease inhibitors can induce severe nausea, vomiting, and other gastrointestinal effects. Similarly, AIDS “wasting syndrome” can literally starve an individual to death.

Investigations with cannabis have revealed its ability to reduce (or eliminate) the nausea and vomiting associated with chemotherapy while also providing an appetite stimulus. The benefits are thus twofold: 1) the patient is able to retain food and maintain body strength, and 2) he or she can tolerate the life-prolonging chemotherapy treatments.

At least eight published studies have confirmed the ability of cannabis and its psychoactive ingredient delta-9-THC to reduce nausea and vomiting. The first appeared in 1975 in The New England Journal of Medicine. It concluded, “THC is an effective anti-emetic for patients receiving cancer chemotherapy.”

The Food and Drug Administration (FDA), in February, 1980 listed 33 studies of cannabis and nausea and vomiting. Most of these experiments involve efforts to determine the proper dosage of THC and several are comparative studies with other standard anti-emetics.

In New Mexico, a state sponsored study has shown the cannabis cigarette to be 30% more effective than THC in relieving nausea and vomiting. Another study, sponsored by the National Cancer Institute (NCI), discovered that inhaled cannabis resulted in a 71% efficacy rate, as opposed to 44% with oral delta-9-THC. These controlled studies have been fortified by “anecdotal” accounts from individuals who have abandoned legal access to THC because they prefer marijuana obtained illegally. These patients report that smoking marijuana seems to bring an almost instantaneous relief.

This is not a new finding. As early as May 1978, researches at a symposium sponsored by the National Cancer Institute (NCI) concluded, “All in all, the cigarette may be the best means of administering the drug.”

In September 1988 the chief administrative law judge of the Drug Enforcement Administration ruled that marijuana has medical value in the treatment of side-effects caused by cancer chemotherapy. His decision was over-ruled by the administrator of the DEA and marijuana remains illegal for medical purposes.”

Cancer Bibliography

Books

Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana, Mary Lynn Mathre, Ed., McFarland Press (1998).

Marijuana Medical Papers, Tod Mikuriya, M.D. (ed.) Medi-Comp Press, (1972).

Cannabinoids as Therapeutic Agents, Raphael Mechoulam (ed.) CRC Press, (1986).

Cancer Treatment & Marijuana Therapy, Robert C. Randall (ed.), Galen Press, (1990).

Marihuana, The Forbidden Medicine, Lester Grinspoon, M.D. and James B. Bakalar, Yale University Press, (1993).

Marijuana and AIDS: Pot, Politics & PWAs in America, Robert C. Randall, Galen Press, (1991).

Journal Articles

Cancer Treatment Reports, 566, 589-592 (1982).

“Cannabinoids for Nausea,” Lancet, January 31, 1981.

Carey, M.P., Burish, T.G., & Brenner, D.E., “Delta-9-THC in Cancer Chemotherapy: Research Problems and Issues,” Annals of Internal Medicine, 99, 106-114 (1983).

Chang, A.E. et al. “Delta-9-Tetrahydrocannabinol as an Antiemetic in Cancer Patients Receiving High-dose Methotrexate,” Annals of Internal Medicine, 91, 819-824 (1979).

Frytek, S. & Moertel, C.G. “Management of Nausea and Vomiting in Cancer Patients,” Journal of the American Medical Association, 245:4, 393-396 (1981).

Harris, L., “Analgesic and Antitumor Potential of the Cannabinoids,” The Therapeutic Potential of Marijuana, Cohen & Stillman (eds.), 299-305 (1976).

Harris, L., Munson, A. & Carchman, R “Anti-tumor Properties of Cannabinoids,” The Pharmacology of Marihuana, Braude & Szara (eds.), 749-762 (1976).

Neidhart, J., Gagen, M., Wilson, H. & Young, D. “Comparative Trial of the Antiemetic Effects of THC and Haloperidol,” Journal of Clinical Pharmacology, 21, 385-425 (1981).