Toxicology and efficacy of tumor-targeting <i>Salmonella typhimurium</i> A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice

Zhang, Yong; Cao, Wenluo; Toneri, Makoto; Zhang, Nan; Kiyuna, Tasuku; Murakami, Takashi; Nelson, Scott D.; Dry, Sarah M.; Li, Yunfeng; Li, Shukuan; Wang, Xiaoen; Ma, Huaiyu; Singh, Arun S.; Eilber, Fritz C.; Hoffman, Robert M.; Zhao, Ming

doi:10.18632/oncotarget.17605

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…Although KST0650 was highly attenuated, it preferentially accumulated in tumor cells in vivo, which was almost comparable with the levels of other well-known cancer targeting strains, such as VNP20009, SL∆ppGpp (∆relA∆spoT), and A1-R 13,18,45 . Despite it could effectively target, colonize, invade tumors, and reduce tumor growth rate slightly as compared with PBS only, which helps prolong mice survival, its tumor-curing effect was not observed obviously in a tumor-bearing mouse model, suggesting that KST0650 monotherapy does not show anti-tumor effect effectively.…”

Section: Discussionmentioning

confidence: 57%

Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

Gao

Jung

Lin

et al. 2020

Sci Rep

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A critical limitation of Salmonella typhimurium (S. typhimurium) as an anti-cancer agent is the loss of their invasive or replicative activities, which results in no or less delivery of anti-cancer agents inside cancer cells in cancer therapy. Here we developed an oxytolerant attenuated Salmonella strain (KST0650) from the parental KST0649 (ΔptsIΔcrr) strain using radiation mutation technology (RMT). The oxytolerant KST0650 strain possessed 20-times higher replication activity in CT26 cancer cells and was less virulent than KST0649. Furthermore, KST0650 migrated effectively into tumor tissues in mice. KST0650 was further equipped with a plasmid harboring a spliced form of the intracellular proapoptotic protein sATF6, and the expression of sATF6 was controlled by the radiation-inducible recN promoter. The new strain was named as KST0652, in which sATF6 protein expression was induced in response to radiation in a dose-dependent manner. This strain was effectively delivered inside cancer cells and tumor tissues via the Salmonella type III secretion system (T3SS). In addition, combination treatment with KST0652 and radiation showed a synergistic anti-tumor effect in murine tumor model with complete inhibition of tumor growth and protection against death. In conclusion, we showed that RMT can be used to effectively develop an anti-tumor Salmonella strain for delivering anti-cancer agents inside tumors.Spontaneous mutations have been extensively used as sources of novel genetic diversity for selecting new improved organisms 1,2 . After the discovery of X-rays and γ-rays, ionizing radiation (IR)-induced mutation breeding is being widely used to generate genetic variability in various organisms 3,4 . After penetrating inside tissues, γ-rays directly disrupt DNA via deposition of energy, or indirectly via ionization, which generates free radicals from radiolysis of water 5-7 . Even though chemical mutagens and ultraviolet irradiation has been widely used for producing bacterial mutants, deletions and insertions are limitedly introduced in the genome. However, the effects of IR cause various types of random DNA mutations including deletions, insertions, and point mutations during DNA repair. The Food and Agriculture Organization of the United Nations (FAO) and the International Atomic Energy Agency (IAEA) Joint Mutant Varieties Database indicated that over 87% of 3,200 mutant variants in 214 plant species, which were developed using RMT, have been released worldwide 8,9 . However, the use of this technique in bacteria is limited, especially for bacteria that are used for medical applications.Salmonella as a potential anti-cancer tool is valuable for treating cancer because of its selective colonizing and proliferative abilities in nonhypoxic and hypoxic regions 10-12 . However, the high virulence of Salmonella limits its application in cancer therapy. Hence, methods of developing attenuated Salmonella strains without

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Section: Discussionmentioning

confidence: 57%

Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

Gao

Jung

Lin

et al. 2020

Sci Rep

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“…Salmonella typhimurium A1‐R ( S. typhimurium A1‐R ) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models . We used the Gene Pulser Transfection Apparatus (Bio‐Rad, 1652100, California, USA) to transfer plasmids into competent attenuated S. typhimurium .…”

Section: Methodsmentioning

confidence: 99%

“…Salmonella typhimurium A1-R (S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. 13 We used the Gene Pulser Transfection Apparatus (Bio-Rad, 1652100, California, USA) to transfer plasmids into competent attenuated S. typhimurium. The instructions indicated that the electrophoretic conditions for attenuated S. typhimurium were the same as for E. coli, so we performed the test according to section 6.1 (E. coli) in the instructions.…”

Section: Animal Experimentsmentioning

confidence: 99%

Urea transport B gene induces melanoma B16 cell death via activation of p53 and mitochondrial apoptosis

et al. 2018

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Urea Transporter B (UT‐B) is a membrane channel protein that mediates the rapid transmembrane transport of urea and participates in urine concentration. Urea Transporter B is expressed in skin, but we found that there is little expression in human melanoma tissue. In this study, we examined the effects of UT‐B overexpression in melanoma. The results indicated that there is no UT‐B mRNA expression in B16 cells, and UT‐B overexpression repressed B16 cell proliferation and induced apoptosis in vitro. We show that UT‐B overexpression causes increased reactive oxygen species production, which may be caused by mitochondria dysfunction. The mitochondrial membrane potential (ΨΔm) was lower in UT‐B‐overexpressing B16 cells. The proteins involved in complexes I, III, IV and V of the respiratory chain were clearly downregulated in UT‐B‐overexpressing B16 cells, which would strongly reduce the activity of the electron transport chain. We found that mitochondrial release of cytochrome C into the cytoplasm also increased, indicating that apoptosis had been activated. In addition, UT‐B overexpression reduced AKT phosphorylation and MDM2 expression and increased p53 expression; p53 activation may be involved in the anticancer effects of UT‐B overexpression. Urea Transporter B overexpression also inhibited tumor growth in vivo. In conclusion, we demonstrated that UT‐B may be related to the occurrence of melanoma and play a role in tumor development.

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“…First approaches aimed to passage Salmonella through cancerous tissue either in vitro or in vivo to improve tumour-targeting by selection. This strategy resulted in the prominent Salmonella vector strains VNP20009 and A1-R (Low et al, 2004;Zhao et al, 2006;Zhang et al, 2017). VNP20009 was evaluated in clinical trials.…”

mentioning

confidence: 99%

“…The Salmonella variant A1-R, on the other hand, appears to be highly potent. This strain is deficient for the amino acids arginine and leucine and has shown great promise in many different types of murine tumours and patient-derived orthotopic xenografts (Hoffman, 2016;Zhang et al, 2017). It will be interesting to follow this particular strain and its performance in clinical trials with human cancer patients.…”

mentioning

confidence: 99%

Tumour‐targeting bacteria‐based cancer therapies for increased specificity and improved outcome

Felgner

Pawar

Kocijancic

et al. 2017

Microbial Biotechnology

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‘You have cancer’ – a devastating diagnosis that still strikes patients hard. Despite substantial improvements of standard therapies over the years, there is still no general cure available. Here, we review the revival of an old concept – the use of bacteria as cancer therapeutics. Bacteria‐mediated tumor therapy has great potential to evolve into a powerful tool against malignant solid tumors.

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Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice

Cited by 21 publications

References 40 publications

Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

Urea transport B gene induces melanoma B16 cell death via activation of p53 and mitochondrial apoptosis

Tumour‐targeting bacteria‐based cancer therapies for increased specificity and improved outcome

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