The therapeutic potential of losartan in lung metastasis of colorectal cancer

Hashemzehi, Milad; Naghibzadeh, Niloufar; Asgharzadeh, Fereshteh; Mostafapour, Asma; Hassanian, Seyed Mahdi; Ferns, Gordon A.; Cho, William C.; Avan, Amir; Khazaei, Majid

doi:10.17179/excli2020-2093

Cited by 9 publications

(5 citation statements)

References 25 publications

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“…Another observed alteration after the combined treatment was a drop in lung weight, which was similar in the 5-FU group and combined treatment group. This effect of 5-FU was described earlier by Hashemzehi et al, after losartan and 5-FU combined treatment [33]. This phenomenon is often seen with drugs that reduce lung metastasis because reducing the number of the metastatic foci in the lungs reduces the weight of the lungs [31].…”

Section: Discussionsupporting

confidence: 57%

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil’s Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer

et al. 2023

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Antimetabolites, especially 5-fluorouracil, are commonly used clinically to treat breast, colon, and other cancers. However, their side effects and inefficiency in monotherapy have prompted further searches for new combinations. Thus, the anticancer effect of 5-fluorouracil (5-FU) and the sulforaphane analogue, 4-isoselenocyanato-1-butyl 4′-fluorobenzyl sulfoxide (ISC), were tested in in vitro and in vivo models of triple-negative breast cancer (TNBC) as a new option for this treatment-resistant and aggressive type of breast cancer. A synergic interaction between 5-FU and ISC was observed in the TNBC in vitro model MDA-MB-231 cell line, which led to enhanced antiproliferative effects. The results of in vitro studies were confirmed by in vivo tests, which demonstrated stronger tumor growth inhibition and additive interactions between 5-FU and ISC in the murine TNBC model. Moreover, the results of the body mass and blood analysis showed the safety of the tested combination. The mechanistic study revealed that the combined treatment triggered apoptosis and necrosis, as well as inhibited cell migration.

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Section: Discussionsupporting

confidence: 57%

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil’s Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer

et al. 2023

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“…Cytotoxicity is one of the common mechanisms of action of anti-cancer therapeutics. The predictive and prognostic significance of p53 and BAX in colorectal cancer and their interactions with the TGF-β pathway have been elucidated in previous works 20 , 37 , 38 . More interestingly, we noticed that the upregulation of these apoptosis-related genes was more significant when the two drugs acted synergically in combination.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of the drugs and their combination in tissue on the activity of superoxide dismutase (SOD), catalase, and the concentration of malondialdehyde (MDA), and total thiol were evaluated according to previous works 20 , 21 .…”

Section: Methodsmentioning

confidence: 99%

Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

Jamialahmadi,

Nazari,

TanzadehPanah

et al. 2023

Sci Rep

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The modulating factors within the tumor microenvironment, for example, transforming growth factor beta (TGF-β), may limit the response to chemo and immunotherapy protocols in colorectal cancer (CRC). In the current study, the therapeutic potential of targeting the TGF-β pathway using Pirfenidone (PFD), a TGF-β inhibitor, either alone or in combination with five fluorouracil (5-FU) has been explored in preclinical models of CRC. The anti-proliferative and migratory effects of PFD were assessed by MTT and wound-healing assays respectively. Xenograft models were used to study the anti-tumor activity, histopathological, and side effects analysis. Targeting of TGF-β resulted in suppression of cell proliferation and migration, associated with modulation of survivin and MMP9/E-cadherin. Moreover, the PFD inhibited TGF-β induced tumor progression, fibrosis, and inflammatory response through perturbation of collagen and E-cadherin. Targeting the TGF-β pathway using PFD may increase the anti-tumor effects of 5-FU and reduce tumor development, providing a new therapeutic approach to CRC treatment.

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“…Losartan is an angiotensin II receptor antagonist extensively used in hypertensive patients. In vitro and in vivo experiments displayed that losartan prevents colorectal cancer [ 65 , 66 ], breast cancer [ 67 ], osteosarcoma [ 68 ] and ovarian cancer [ 69 ] progression in mice. In addition, losartan can enhance PD1ab therapy efficacy in breast cancer [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy

Sun,

Zhang,

et al. 2024

J Orthop Surg Res

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Purpose Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. Methods We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. Results Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. Conclusion Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

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The therapeutic potential of losartan in lung metastasis of colorectal cancer

Cited by 9 publications

References 25 publications

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil’s Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil’s Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer

Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy

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