Tumoricidal effects of mycobacterium ulcerans toxin on murine adenocarcinoma (C3HBA)

Heggers, John P.; Robson, Martin C.; Yetter, Joseph F.; Kreig, Richard E.; Jennings, Paul B.

doi:10.1002/jso.2930110210

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…Indeed, the potent toxicity profile of ML has prompted its development for therapeutic use as an anti-tumor agent. 24,25 We observed dense clusters of PGP 9.5 positive neurons with profuse neurite outgrowth in control cultures, while ML-treated cultures showed vastly reduced numbers of neurons with shortened, faintly positive, degenerating neurites. These features are similar to those previously described with the chemotherapy drug oxaliplatin in DRG neuronal cultures, due to a toxic effect presenting as dying back of neurites.…”

Section: Discussionmentioning

confidence: 85%

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Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons

et al. 2016

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BackgroundMycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone.ResultsMorphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401.ConclusionMycolactone induces toxic effects in DRG neurons, leading to impaired nociceptor function, neurite degeneration, and cell death, resembling the cutaneous hypoalgesia and nerve damage in individuals with M. Ulcerans infection.

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Section: Discussionmentioning

confidence: 85%

“…Indeed, the potent toxicity profile of ML has prompted its development for therapeutic use as an anti-tumor agent. 24,25…”

Section: Discussionmentioning

confidence: 99%

Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons

et al. 2016

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“…While avoiding generalizations regarding the relative efficacy of any particular treatment, the following report is an example of success in immunotherapeutic control of metastasis. The injections of nonspecific adjuvants directly into the primary mammary carcinomas of C3HBA mice induced extensive necrosis of the primary tumor and also reduced the incidence of spontaneous hepatic and pulmonary metastases (73). The authors attributed this inhibition to increased infiltration by mononuclear cells.…”

Section: Hnmunotherap)' and Metastasismentioning

confidence: 97%

Host resistance to metastasis from mouse mammary carcinomas

Vaage

Glaves-Rapp

1983

Cancer Metast Rev

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Although undisturbed primary mouse mammary tumors may give rise to overt metastases, these have generally been observed near the terminal stage of progressive tumor growth. Unlike malignant breast disease in women, metastases are seldom the cause of death in mice, and in some strains as few as 2% of mammary tumor hosts may be affected (1). Highly metastatic tumors may, of course, be found, and hosts of the mammary carcinoma WHT all develop metastases (2). Evidence from animal models suggests that host defense reactions against immunogenic tumors may affect the incidence of metastatic spread (3-5). But nonimmunogenic and weakly immunogenic tumors probably represent the majority of mammary carcinomas (2, 6, 7), and this class was once considered outside control by the host. However, natural protective factors are also known which may prevent metastasis independently of specific antitumor immunity (8-10). There are therefore most likely several different biological factors and mechanisms which prevent circulating, viable cancer cells from developing into metastases. But one can not yet generalize whether natural resistance factors or induced resistance factors are the most important, or whether any resistance factors are as important in preventing metastases as is the basic unacceptability of cells in heterotopic locations. This review will not attempt to present a comprehensive analysis of cell-mediated and humoral immunity to mouse mammary tumors because this topic has recently been exhaustively treated in the reviews by Stutman (11) and Blair (12). We will focus primarily on information from in vivo investigations of the role of host resistance in the control of mammary tumor cells progressing through successive levels of metastasis from the primary tumor, through lymphatic or hematogenous dissemination, to colonization of distant organs.

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