Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella Typhimurium strain

Yu, Bin; Yang, Mei; Shi, Lei; Yao, Yihong; Jiang, Qinqin; Li, Xuefei; Tang, Lei-Han; Zheng, Bo; Yuen, Kwok‐Yung; Smith, David K.; Song, Erwei; Huang, Jian

doi:10.1038/srep00436

Cited by 130 publications

(125 citation statements)

References 47 publications

(102 reference statements)

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“…Hypoxia-targeted therapies such as gene therapy (using a promoter highly responsive to Hypoxia Inducible Factor-1 [HIF-1]), recombinant anaerobic bacteria (whose spores activate in necrotic centers of tumors and kill tumor tissue) and hypoxia-activated pro-drugs (HAPs) are all under investigation. 1,5 HAPs are administered in an inactive form and are reduced to their active metabolites within hypoxic regions of tumors. 1 Once activated they may diffuse to act against cells in neighboring tumor regions ("the bystander effect").…”

mentioning

confidence: 99%

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Saggar

Tannock

2013

Intl Journal of Cancer

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Many chemotherapy drugs have poor therapeutic activity in regions distant from tumor blood vessels because of poor tissue penetration and low cytotoxic activity against slowly-proliferating cells. The hypoxia-activated pro-drug TH-302 may have selective toxicity for hypoxic and neighboring cells in tumors. Here we characterize the spatial distribution and ability of TH-302 to selectively target hypoxic regions and complement the effect of doxorubicin and docetaxel by modifying biomarker distribution. Athymic nude mice bearing human breast MCF-7 or prostate PC-3 tumors were treated with doxorubicin or docetaxel respectively and TH-302 alone or in combination. Biomarkers of drug effect including cH2aX (a marker of DNA damage), cleaved caspase-3 or -6 (markers of apoptosis) and reduction in Ki-67 (a marker of cell proliferation) were quantified in tumor sections in relation to functional blood vessels (recognized by DiOC7) and hypoxia (recognized by EF5) using immunohistochemistry. cH2aX expression at 10 min and cleaved caspase-3 or -6 at 24 hr after doxorubicin or docetaxel decreased with increasing distance from tumor blood vessels, with minimal expression in hypoxic regions; maximum reduction in Ki67 levels was observed in regions closest to vasculature at 24 hr. TH-302 induced maximal cell damage in hypoxic and neighboring regions, but was also active in tumor regions closer to blood vessels. TH-302 given 4 hr before doxorubicin or docetaxel increased DNA damage and apoptosis throughout the tumor compared to chemotherapy alone. When given with doxorubicin or docetaxel, TH-302 complements and enhances anticancer effects in both perivascular and hypoxic regions but also increases toxicity.

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mentioning

confidence: 99%

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Saggar

Tannock

2013

Intl Journal of Cancer

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“…The bacterial YB1 strain was cultured in lysogeny broth medium overnight (12 to 16 h) (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) supplemented with chloramphenicol and 2,3-diaminopropionic acid (Sigma-Aldrich; Merck KGaA) at 37˚C (8).…”

Section: Methodsmentioning

confidence: 99%

“…The engineered YB1 strain only survives under hypoxic conditions (8). However, whether YB1 may invade M2 macrophages under hypoxic conditions remains unknown.…”

Section: Macrophage Infiltration In Breast Tumor Tissuesmentioning

confidence: 99%

“…In a previous study, a synthetic biology approach was used to generate the novel Salmonella typhimurium strain YB1 (YB1) (8). This bacterium specifically colonizes and proliferates in the hypoxic/necrotic areas of the tumor, but avoids normal organs and retards tumor growth (8). Furthermore, a previous study reported that numerous macrophages accumulate in breast tumors and are associated with a poor prognosis (9).…”

Section: Introductionmentioning

confidence: 99%

“…Bacteria, including Bifidobacterium (1,2), Clostridium (3) and Salmonella have been demonstrated to preferentially target and replicate in the hypoxic and necrotic regions of a tumor, resulting in tumor repression (4)(5)(6)(7). In a previous study, a synthetic biology approach was used to generate the novel Salmonella typhimurium strain YB1 (YB1) (8). This bacterium specifically colonizes and proliferates in the hypoxic/necrotic areas of the tumor, but avoids normal organs and retards tumor growth (8).…”

Section: Introductionmentioning

confidence: 99%

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An obligatory anaerobic Salmonellaï¿½typhimurium strain redirects M2 macrophages to the M1 phenotype

Yang

Wang

et al. 2018

Oncol Lett

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Abstract.A genetically engineered Salmonella typhimurium strain that may be applied in the medically useful therapeutic strategy of using bacterial agents to target breast cancer in a tumor-bearing nude mouse model has been previously reported. Furthermore, immune cell accumulation in breast tumor types has been observed, particularly distributed in regions surrounding the bacteria. M2 macrophages are associated with breast cancer aggressiveness, whereas M1 macrophages are prone to devouring bacteria and killing cancer cells. Therefore, this engineered tumor-targeting salmonella strain was used in an attempt to reverse the phenotype of M2 macrophages into the M1 phenotype. Subsequent to the co-culture of M2 macrophages with the bacteria for a short time, >50% of the M2 macrophages were invaded by bacteria. These M2 macrophages exhibited a decreased expression of mannose receptor (an M2 phenotypic marker) and increased expression of human leukocyte antigen-antigen D related (an M1 phenotypic marker). The results of the present study indicated that differentiated M2 macrophages may be redirected into the M1 phenotype following exposure to the engineered bacteria stimulus. This effect may be a potential mechanism by which bacteria retard tumor growth. Thus, this engineered bacterium may be a useful candidate for targeting and redirecting M2 macrophages into the M1 phenotype.

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The Rational Engineered Bacteria Based Biohybrid Living System for Tumor Therapy

Wang,

Feng,

Shi

et al. 2024

Adv Healthcare Materials

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Living therapy based on bacterial cells has gained increasing attention for their applications in tumor treatments. Bacterial cells can naturally target to tumor sites and active the innate immunological responses. The intrinsic advantages of bacteria attribute to the development of biohybrid living carriers for targeting delivery toward hypoxic environments. The rationally engineered bacterial cells integrate various functions to enhance the tumor therapy and reduce toxic side effects. In this review, the antitumor effects of bacteria and their application are discussed as living therapeutic agents across multiple antitumor platforms. The various kinds of bacteria used for cancer therapy are first introduced and demonstrated the mechanism of antitumor effects as well as the immunological effects. Additionally, this study focused on the genetically modified bacteria for the production of antitumor agents as living delivery system to treat cancer. The combination of living bacterial cells with functional nanomaterials is then discussed in the cancer treatments. In brief, the rational design of living therapy based on bacterial cells highlighted a rapid development in tumor therapy and pointed out the potentials in clinical applications.

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Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella Typhimurium strain

Cited by 130 publications

References 47 publications

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

An obligatory anaerobic Salmonellaï¿½typhimurium strain redirects M2 macrophages to the M1 phenotype

The Rational Engineered Bacteria Based Biohybrid Living System for Tumor Therapy

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