Tagged: Mice

Melatonin in Cancer Therapy: Lessons From 50 Years of Research

December 28, 2023

In a new research perspective, researchers discuss melatonin’s effects on cancer and the key importance of the timing of administration.

Melatonin in Cancer Therapy: Lessons From 50 Years of Research

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In the realm of cancer research, the potential of melatonin as an anti-cancer agent has garnered significant attention. Over the past 50 years, numerous studies have been conducted to investigate the effects of melatonin on tumor growth and development in mice. These studies have provided valuable insights into the complex relationship between melatonin and carcinogenesis.

In a new research perspective, researchers Vladimir N. Anisimov and Alexey G. Golubev from N.N. Petrov National Medical Research Center of Oncology wrote about the history of studies of melatonin effects on cancer in mice. Their paper was published in Oncotarget on December 12, 2023, entitled, “Melatonin and carcinogenesis in mice: the 50th anniversary of relationships.”

Early Discoveries and Controversies

In 1973, Vladimir N. Anisimov and his coauthors made a groundbreaking discovery by demonstrating the inhibitory effect of melatonin on transplantable mammary tumors in mice. This pivotal study laid the foundation for subsequent investigations into the potential anti-cancer properties of melatonin. However, early studies encountered controversies regarding the consistency of melatonin’s effects on in vivo cancer models. The lack of consistency in these studies prompted further exploration of the factors influencing melatonin’s efficacy.

Importance of Timing in Melatonin Administration

One of the crucial findings in melatonin research is the significant impact of timing in melatonin administration. Bartsch and Bartsch demonstrated that the effects of melatonin on cancer in mice depend on the time of treatment. The administration of melatonin in the morning stimulated tumor growth, while late afternoon administration inhibited it. This observation highlighted the importance of considering animal conditions and the systemic effects of melatonin when evaluating its anti-cancer properties. These systemic effects may not be evident in cell cultures or ex vivo explants.

Murine Models for Melatonin and Cancer Studies

Murine models have played a pivotal role in elucidating the effects of melatonin on various types of cancer. These models have provided valuable insights into the potential utility of melatonin in oncology. Some of the notable murine models include mice grafted with murine tumors, chemically induced tumors, spontaneous carcinogenesis in mice, transgenic HER2/neu oncogene-bearing mice, and nude mice grafted with human prostate tumors. These models have allowed researchers to evaluate not only the effects of melatonin on cancer development but also its impact on the efficacy and side effects of anticancer therapies.

Melatonin’s Effects on Spontaneous Tumor Incidence

One intriguing finding in murine studies is the effect of melatonin on spontaneous tumor incidence. Anisimov et al. showed that lifelong treatment of mice with melatonin decreased the incidence of spontaneous tumors, particularly mammary carcinomas, but only at a low concentration of melatonin in drinking water. Interestingly, this effect was not observed at a high melatonin concentration. These findings suggest that the dose of melatonin may play a crucial role in its anti-cancer effects.

Melatonin’s Role in Potentiating Cytotoxic Therapy

Another area of interest in melatonin research is its potential to enhance the efficacy of cytotoxic therapy against tumors. Panchenko et al. demonstrated that the timing of melatonin administration relative to cytotoxic drug administration significantly influenced its potentiating effect on cytotoxic therapy in HER2/neu transgenic mice. This finding highlights the importance of optimizing the timing of melatonin administration in combination with other cancer treatments.

Melatonin’s Protective Effects on Side Effects

Beyond its direct anti-cancer effects, melatonin has shown promise in alleviating the side effects of cytotoxic drugs and radiation therapy. Several murine models have demonstrated the ability of melatonin to mitigate the side effects associated with these treatments. For example, melatonin was shown to alleviate the depression syndrome in mice treated with the alkylating agent temozolomide used in brain cancer therapy. Additionally, melatonin has been found to protect against ovarian follicle depletion caused by cisplatin, a commonly used chemotherapy drug. These findings suggest that melatonin may have a broader role in cancer treatment by reducing the adverse effects of traditional therapies.

Melatonin’s Effects on Metastasis and Epithelial-Mesenchymal Transition

Metastasis is a significant challenge in cancer treatment, and melatonin has shown promise in inhibiting metastatic spread. In nude mice grafted with human gastric cancer, melatonin was found to suppress lung metastases development by inhibiting the epithelial-to-mesenchymal transition (EMT). The inhibition of EMT by melatonin has also been observed in other murine models, highlighting its potential as an anti-metastatic agent. Given the crucial role of EMT in primary cancer and metastasis development, these findings have significant implications for oncology research.

Melatonin and Inflammation

Chronic inflammation is increasingly recognized as a contributing factor in cancer development and progression. Melatonin has been found to modulate inflammatory processes in murine models. In a murine model of low-grade inflammation, melatonin inhibited EMT), suggesting a potential role in suppressing cancer-related inflammation. While the direct anti-inflammatory effects of melatonin require further investigation, these findings shed light on the multifaceted mechanisms through which melatonin may exert its anti-cancer effects.

Clinical Applications and Promising Results

The employment of melatonin in clinical settings beyond its established fields does not require licensing, making it more readily accessible for testing novel applications in cancer treatment. Promising clinical results have already been reported, such as increased overall survival in prostate cancer patients with poor prognosis after combined hormone radiation treatment. These findings highlight the potential translational impact of murine studies and underscore the importance of continued research to fully understand the clinical implications of melatonin in cancer therapy.

Conclusion

Over the past 50 years, murine models have provided valuable insights into the relationship between melatonin and carcinogenesis. These studies have shed light on the importance of timing in melatonin administration, its effects on tumor incidence and metastasis, as well as its role in potentiating cytotoxic therapy and mitigating side effects. While the precise mechanisms underlying melatonin’s anti-cancer effects require further exploration, the promising results observed in both preclinical and clinical studies warrant continued investigation. As researchers continue to unravel the complexities of melatonin’s interactions with cancer, new opportunities for therapeutic interventions may emerge, offering hope for improved cancer treatment outcomes.

“The […] main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over [the] counter and thus needs no licensing for its applications in oncology.”

Click here to read the full research perspective in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Oncotarget

Chemical in Sunscreen Promotes Breast Cancer in Diet-Dependent Manner

November 18, 2021

The bioactivity of oxybenzone—a harmful chemical often found in sunscreens—was examined within mouse models of breast cancer in high- and low-fat dietary contexts.

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Oxybenzone (benzophenone-3; BP-3) is a toxic endocrine-disrupting chemical (EDC). Alarmingly, this chemical has been identified as a common ingredient in some brands of sunscreen. Oxybenzone can often be found in humans, household dust, fish and, due to its widespread human use, the water environment—causing harm to coral reefs and other murine life. Previous studies have shown that environmental toxins and estrogenic chemicals have emerged as potential culprits in the promotion of breast cancer. Furthermore, oxybenzone has been known to have estrogenic and anti-estrogenic properties.

“Although BP-3 has a very short half-life, its presence is widespread in human urine [9], in as much as 98% of the general U.S. population [13].”

Researchers from the Breast Cancer and the Environment Research Program at Michigan State University studied the diet-dependent effects of oxybenzone in mouse models of mammary tumorigenesis during puberty and adulthood. Their paper was published by Oncotarget in 2020, and entitled, “Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.”

“We [previously] demonstrated enhancement of mammary tumorigenesis by a diet high in saturated animal fat (HFD) [5–8]. Thus, examination of the activity of EDCs in a dietary context may provide additional insight into the potential role of EDCs in promoting breast cancer.”

The Study

In the current study, the team employed the Trp53–null transplantation of a basal-like breast cancer mouse model. The researchers previously demonstrated that proliferative, inflammatory and angiogenic activity in the mammary gland can be modulated by estrogen and a high-fat diet (HFD). Therefore, both pubertal and adult mice were placed on either low- or high-fat diets. After one week, study mice were ovariectomized, given time for recovery and the natural dissipation of endogenous hormones, and then treated for five days with either saline (control) or 17β-estradiol (E2).

Next, the estrogenic or anti-estrogenic effects of oxybenzone were examined in these mice under three dietary conditions: mice fed a life-long low-fat diet (LFD), mice fed a LFD during puberty and then a HFD in adulthood (LFD-HFD) and finally, mice fed a HFD during puberty and then a LFD in adulthood (HFD-LFD). Mice in LFD-HFD and HFD-LFD groups were fed their initial diet from three to 10 weeks of age, and were then switched to the alternative diet. Half of these mice were injected with oxybenzone and the other half (control) were injected with saline.

“We found that BP-3 had complex effects that were dependent upon dietary regimen and tumor histopathology.”

Results

Consistent with their previous studies, the researchers found that most of the tumors developed were epithelial in histological composition, and few were spindle cell carcinomas. They found that oxybenzone reduced the tumorigenesis of epithelial tumors in LFD mice. The LFD-HFD combination resulted in more spindle cell tumors compared to the life-long LFD mice. Oxybenzone treatment increased the tumorigenesis of epithelial tumors in mice fed the LFD-HFD.

“Kaplan-Meier analysis revealed that BP-3 reduced tumorigenesis of epithelial tumors in mice fed LFD (Figure 3A). On the other hand, consistent with the increased proportion of epithelial tumors, BP-3 was promotional for epithelial tumorigenesis in mice fed LFD-HFD (Figure 3C), while reducing spindle cell tumorigenesis (Figure 3D).”

Researchers saw that proliferation was increased by oxybenzone treatment most significantly in the mammary glands of 26-week-old HFD mice. Curiously, oxybenzone treatment increased the number of lesions only in mice fed the HFD-LFD. The researchers note that, in this study and others, a “pubertal window of susceptibility” was observed, reinforcing the important notion that puberty is a highly sensitive window of time for poor diets and adverse exposures to environmental toxins. Ultimately, the team found that oxybenzone enhances estrogen-stimulated breast cancer cell proliferation in pubertal mice fed a HFD.

“Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology.”

Conclusion

Collectively, the researchers’ findings suggest that exposure to oxybenzone has adverse consequences in mammary tumorigenesis. The degree of severity appeared to be modulated differently among the three dietary regimens studied. Mice fed a HFD in adulthood experienced a decrease in tumor cell apoptosis and an increase in tumor vascularity and tumor cell proliferation. They note that there is future value in exploring the differences between pubertal and adult exposure to oxybenzone on a constant diet regimen.

“This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.”

Click here to read the full scientific study, published by Oncotarget.

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Oncotarget

Trending with Impact: Bacterial Therapy Experiments in Prostate Cancer

January 21, 2021

Researchers reveal their positive findings from a study of bacterial cancer therapy using a strain of Salmonella typhimurium in mouse-modeled prostate cancer.

PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope. - Image — PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

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Over the past few decades, numerous studies have emerged using the promising strategy of bacteria as vehicles to deliver drugs or genes in tumor‐targeted therapies. Researchers say that bacterial cancer therapy may be able to overcome some of the limitations that conventional cancer therapy is stunted by, including the development of drug resistance.

Researchers in this study—from Yale University in Connecticut, the University of Missouri, the Harry S. Truman Memorial Veterans Hospital, and the Cancer Research Center in Missouri, and DeSales University in Pennsylvania, U.S.—used a Salmonella typhimurium strain (CRC2631) of bacteria (previously reported to have tumor-targeting capabilities) in prostate cancer-positive mouse-models and evaluated its toxicity, targeting ability, and genetic stability.

“Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and autochthonous mouse model of aggressive prostate cancer, TRAMP (Transgenic Adenocarcinoma of Mouse Prostate).”

“The B6FVB TRAMP model recapitulates some of the key genetic aspects of human prostate cancer.”

The Study

“VNP20009 is considered as the safety benchmark in bacterial cancer therapy development because it has been safely administered in human cancer patients [7, 30].”

“To determine the safety profile of CRC2631, we performed CRC2631 and VNP20009 comparative toxicological studies in TRAMP animals.”

The team focused on measuring toxicity through treatment-related weight loss and lethality. Groups of 14-week-old B6FVB TRAMP-positive mice were scanned using magnetic resonance imaging. Four mice were dosed with CRC2631, and four were dosed with VNP20009; both treated four times per week. Mice were weighed and monitored daily for four weeks.

Since the CRC2631 bacteria are cleared out through the liver, the researchers also sought to establish the impact of CRC2631 on liver pathology in this bacterial cancer therapy. Two groups of 31-week-old B6FVB TRAMP-positive mice were observed, one treated with four doses of CRC2631 and the other with saline (the control group) at three-day intervals. They used histological staining in the liver to observe differences in necrosis, inflammation, and extramedullary hematopoiesis between CRC2631 and the control group. The team then tested for lethality and the maximum tolerated dose of CRC2631.

“Next, we sought to determine the in vivo tumor-targeting capability of CRC2631 in TRAMP animals.”

Using fluorescence imaging and a chloramphenicol resistance cassette, researchers were able to observe the biodistribution of CRC2631 to determine its tumor-targeting capability in TRAMP-positive mice. Since they knew that CRC2631 is filtered through the liver and that enriched colonies may be found here, researchers used the liver as a way to compare the bacterial load in tumor tissues.

The researchers also tested CRC2631’s genetic stability by gauging its likelihood of regaining toxicity and/or losing tumor targeting capability by performing longitudinal, whole genome sequencing and short nucleotide polymorphism analyses.

“To determine the genetic stability of CRC2631 inside the host, we performed longitudinal whole genome sequencing and short nucleotide polymorphism (SNP) analyses of CRC2631 prior to treatment and tumor-passaged CRC2631 in B6 TRAMP (+) mice.”

In vitro, CRC2631 directly kills prostate cancer cells, however, in vivo, it does not lead to decreased tumor burden. The researchers believe this may be due to the effects of some kind of resistance mechanism in vivo, and tested a combined treatment method of CRC2631 and Invivomab—a checkpoint blockade—in the mouse model.

“CRC2631 targets and directly kills murine and human prostate cancer cells in vitro (Supplementary Figure 2), raising the possibility that unknown resistance mechanisms protect tumor cells from CRC2631-mediated cell death in vivo.”

Results

Researchers explain that in the first two weeks of the study, mice treated with CRC2631 and VNP20009 lost a comparable amount of weight. However, in the second half of the study, VNP20009-treated animals lost progressively more weight than those treated with CRC2631. This revealed that CRC2631 is less toxic than VNP20009.

“Consistent with CRC2631 being less toxic than VNP20009, the median survival time was 142 days for VNP20009 compared to 186 days for CRC2631 (Figure 1F).”

After evaluating effects in the liver from CRC2631, they found no differences between CRC2631 and the control group in liver necrosis, inflammation, or extramedullary hematopoiesis.

“Thus, in contrast to VNP20009, CRC2631 does not cause overt liver pathology.”

They established the maximum tolerated dose to be two doses of 5 × 10^7 colony forming units, administered three days apart. In the model used in fluorescence imaging, they found that CRC2631 was significantly colonized in the tumor tissue of mice when compared to colonization in the liver and, as the dosage increased, CRC2631 quantities in tumor tissues also increased.

“Taken together, these data indicate that CRC2631^iRFP720-cat targets primary tumors and metastases.”

Researchers revealed that it would take approximately 9375 days for CRC2631 to acquire a potential mutation in any specific gene. They determined CRC2631 to be a genetically stable tumor-targeting mechanism. Next, they collected results from the CRC2631 and Invivomab immune checkpoint blockade combination.

“We turned our focus to an interaction between CRC2631 and immune cells and asked whether tumor-targeted CRC2631 generates an anti-tumor immune response that tumors rapidly inhibit via immune checkpoint mechanisms.”

They found that tumor burdens were significantly reduced in the combination treatment method, and ultimately, that CRC2631 treatment with a checkpoint blockade combination reduces the metastatic burden in mouse-modeled prostate cancer.

Conclusion

The study as a whole revealed to the researchers that CRC2631 safely targets primary tumors and metastases, is less toxic than VNP20009, does not cause overt liver pathology, and that, in combination with an immune checkpoint blockade such as Invivomab, it reduces metastatic burden in vivo in B6FVB TRAMP-positive mice.

“These findings indicate that CRC2631 is a genetically stable biologic that safely targets tumors. Moreover, tumor-targeted CRC2631 induces anti-tumor immune activity and concordantly reduces metastasis burden in the setting of checkpoint blockade.”

With more research, this method may soon be studied as an effective clinical treatment option for human prostate cancer.

Click here to read the full scientific study, published in Oncotarget.

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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.