"Fasting" is a new direction for liver cancer treatment to break the situation?

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“Fasting” is a new direction for liver cancer treatment to break the situation?

These days, keeping your mouth shut can also cure diseases, that is, dietary intervention therapy.

And in this dietary intervention, fasting-mimicking diet (FMD) is the sweet spot!

FMD is characterized by low levels of carbohydrates and protein, relatively high fat, and thus a calorie restriction of 50% or less of a standard diet. In recent years, many animal experiments have confirmed that FMD can prolong the lifespan of mice, reduce and delay the occurrence of cancer, alleviate autoimmune diseases, and regulate intestinal flora [1-4].

Based on this, the research and development of FMD drugs and the combined treatment of FMD and other drugs have also attracted the attention of scientists, in order to provide a convenient and effective strategy for clinical treatment.

Not long ago, a paper published in the journal Science Advances proposed that FMD and sorafenib, a targeted drug for hepatocellular carcinoma (HCC), have a synergistic effect in the treatment of HCC .

Andreas Prokesch from the University of Graz, Austria, and his colleagues found that FMD not only enhanced the efficacy of sorafenib, but also improved the resistance of sorafenib, and this synergy depends on the tumor suppressor gene p53 normal expression [5].

"Fasting" is a new direction for liver cancer treatment to break the situation?

Liver cancer is one of the most common malignant tumors, the fifth most common cancer in some countries, and the second leading cause of cancer death. In primary liver cancer, HCC accounts for 75%-85% and is the main form of liver cancer [6].

Sorafenib is a commonly used drug for HCC that cannot be treated by surgical resection . This anti-angiogenesis-targeted drug was able to extend overall survival by 3 months. Unfortunately, due to the insurmountable problem of drug resistance , there have been no clinical cases of recovery from sorafenib monotherapy [7,8].

Therefore, sorafenib urgently needs to find a new way in the treatment of HCC. And affordable, healthy and pollution-free FMD is undoubtedly a good partner for combined treatment.

This time, Prokesch and his colleagues examined the combination therapy of sorafenib and FMD.

First, they selected a human hepatoma cell line, HepG2, a highly resistant HCC cell to sorafenib, and injected it into mice subcutaneously (NMRI). They were randomly divided into 4 groups for different treatments, namely placebo + free diet group, placebo + FMD group, sorafenib + free diet group, and sorafenib + FMD group.

When feeding the mice with FMD, the researchers opted for a 5:2 fasting regimen (fasting 2 days a week) rather than every other day.

They found that while both FMD regimens resulted in short-term reductions in blood sugar levels and body weight in mice , weight remained stable in the long-term when mice were fed a 5:2 fasting regimen ; whereas mice fed an alternate-day fasting regimen , The body weight shows an irreversible downward trend .

If you take long-term treatment, I am afraid that the mouse will be hungry before the disease is cured.

"Fasting" is a new direction for liver cancer treatment to break the situation?

C, D: 5:2 fasting and weight change

E, F: Alternate-day fasting and weight change

After more than 4 weeks of treatment, the researchers found that monotherapy with sorafenib or FMD only showed a trend of tumor reduction, with no significant change in tumor size.

In contrast, when the combined treatment was combined, the effects were superimposed, and the tumor growth of the mice in the sorafenib + FMD group was significantly inhibited, and the overall body weight was not affected.

This suggests that FMD may reduce sorafenib resistance with a synergistic effect.

"Fasting" is a new direction for liver cancer treatment to break the situation?

The weight of mice in the Fasted/Sfd (FMD + Sorafenib) group did not change, and tumor growth was inhibited

Prokesch and his colleagues also cultured the HepG2 cell line in vitro and showed that the apoptotic signal was already elevated 4 hours after the addition of sorafenib to the FMD-mimicking medium ; the viability of HepG2 cells increased with Sorafenib The dose of fenib decreased, and the number of cytotoxicity and apoptosis increased with the increase of dose .

This result was confirmed again in the in vitro culture of patient-derived drug-resistant HCC organoids.

"Fasting" is a new direction for liver cancer treatment to break the situation?

In FMD mode, the efficacy of sorafenib is proportional to the dose

(GM: complete medium; SM: simulated FMD medium)

In conclusion, sorafenib and FMD have a synergistic effect in the treatment of HCC, and the combined treatment of the two can solve the problem of resistance of HCC cells to sorafenib and improve the efficacy.

Mechanistically, sorafenib is an atypical inhibitor of mitochondrial respiration, which can lead to impaired oxidative phosphorylation (OXPHOS) process in cancer cells, turning cancer cells into anaerobic respiration , which provides energy by enhancing glycolysis [ 9,10] (that is, the Warburg effect [11]).

Glycolysis requires the consumption of large amounts of glucose. In vitro experiments with HepG2 cells, Prokesch and his colleagues found that cancer cell viability after sorafenib treatment gradually recovered with increasing glucose doses .

When the glucose concentration in the medium was 3 mM, cell viability did not improve; when glucose was added to 5 mM, about 50% of the cancer cells recovered.

In xenograft experiments in mice, they found that FMD-fed mice significantly reduced blood sugar levels to about 3 mM. This shows that FMD is enough to reduce the blood glucose in vivo to a certain level and reduce the survival rate of HCC cells after the use of sorafenib .

I: In vitro experiments, when the glucose level is 3mM, can maintain very low cell viability

J, K: FMD is sufficient to reduce blood glucose levels to 3 mM in vitro

To put it simply, sorafenib blocks the aerobic respiration of HCC cells and converts them to glycolysis; while FMD will cause the glycolysis of HCC cells to have no sugar available. approaching a dead end .

The researchers further studied and found that FMD can not only reduce blood sugar, but also block the AKT/mTOR signaling pathway and increase the sensitivity of HCC cells to sorafenib.

Notably, p53 can play a key role in the synergistic treatment of FMD+sorafenib by regulating the expression of glucose transporters and pro-apoptotic proteins .

When the p53 gene in HepG2 cells was knocked out, the “fit attack” of FMD and sorafenib on HepG2 cells was ineffective without significant reduction in cell viability or enhanced cytotoxicity. Once p53 was re-expressed, FMD again increased the sensitivity of HepG2 cells to sorafenib.

Synergy of p53 signaling-dependent FMD and sorafenib in HCC therapy

In previous studies, Prokesch and colleagues used sorafenib-resistant HCC cells. Finally, they again demonstrated the synergistic efficacy of FMD+sorafenib in a mouse model of non-drug-resistant HCC cell transplantation and an orthotopic HCC mouse model.

Efficacy of FMD+sorafenib in orthotopic HCC mice

(p53WT: p53 normal expression; p53KO: p53 knockout)

Overall, Prokesch and colleagues found that a fasting-mimicking diet enhanced the efficacy of sorafenib in hepatocellular carcinoma treatment and increased the sensitivity of hepatocellular carcinoma cells to sorafenib.

This synergy depends on the normal expression of p53 signaling in cancer cells .

The researchers say the combination of sorafenib and a fasting-mimicking diet amounts to a “double whammy” on cancer cell metabolism .

Sorafenib blocks the aerobic respiration of cancer cells, simulating a fasting diet and depriving cancer cells of the substrate for glycolysis, leaving cancer cells with nowhere to go for energy.

The findings of this study not only provide a new treatment strategy for patients with advanced hepatocellular carcinoma, but also demonstrate the possibility of a clinical application of fasting-mimicking diet therapy in hepatocellular carcinoma .

At the same time, it also suggests that in the future clinical use of the combination therapy of simulated fasting diet + sorafenib, the expression of p53 in patients is an indicator that cannot be ignored .

references:

[1] Wei, M. et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci. Transl. Med. 9, eaai8700 (2017).

[2] Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).

[3] Choi, I. Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 15, 2136–2146 (2016).

[4] A. Nencioni, I. Caffa, S. Cortellino, VD Longo, Fasting and cancer: Molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).

[5]https://www.science.org/doi/10.1126/sciadv.abh2635

[6] JM Llovet, RK Kelley, A. Villanueva, AG Singal, E. Pikarsky, S. Roayaie, R. Lencioni, K. Koike, J. Zucman-Rossi, RS Finn, Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 6 (2021).

[7]J. M. Llovet, R. Montal, D. Sia, R. S. Finn, Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018).

[8]Y. J. Zhu, B. Zheng, H. Y. Wang, L. Chen, New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol. Sin. 38, 614–622 (2017).

[9]L. Fiume, M. Manerba, M. Vettraino, G. Di Stefano, Effect of sorafenib on the energy metabolism of hepatocellular carcinoma cells. Eur. J. Pharmacol. 670, 39–43 (2011).

[10]C. Jian, et al. Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab. 31, 892–908.e11 (2020).

[11]N. N. Pavlova, C. B. Thompson, The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

“Fasting” is a new direction for liver cancer treatment to break the situation?

(source:internet, reference only)

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