Autophagy Paradox of Cancer: Role, Regulation, and Duality

Verma, Amit Kumar; Bharti, Prahalad Singh; Rafat, Sahar; Bhatt, Deepti; Goyal, Yamini; Pandey, Kamlesh Kumar; Ranjan, Sanjeev; Almatroodi, Saleh A.; Alsahli, Mohammed A; Rahmani, Arshad Husain; Almatroudi, Ahmad; Dev, Kapil

doi:10.1155/2021/8832541

Cited by 35 publications

(28 citation statements)

References 170 publications

(135 reference statements)

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“…Our findings also suggested that lurasidone partially sensitizes cancer cells to osimertinib by increasing autophagy. Autophagy can have various roles as it may be suppressed or increased depending on the phase of tumor formation and the actual state of the tumors (29,30). In accordance with our findings, some studies suggest that increased autophagy leads to cell death following EGFR-TKI treatment (18,31).…”

Section: Lurasidone Sensitizes Various Tumor Cells To Osimertinib the Indicated Cancer Cells Were Cultured With Or Without 2 μM Osimertinsupporting

confidence: 89%

Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin

et al. 2021

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Background/Aim: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. Materials and Methods: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. Results: Within a nontoxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. Conclusion: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.Cancer is one of the major causes of mortality and remains an important social burden worldwide. However, there is no true cure for cancer to this day (1). Recent targeted therapies, such as entrectinib and alectinib, which are specific to important molecules in tumors, such as tyrosine receptor kinase (TRK) and anaplastic lymphoma kinase (ALK), are shown to be highly effective (2, 3). Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) that targets EGFR mutation, and is commonly used worldwide as it is highly effective and causes only minor adverse events (4, 5). However, the effect of EGFR-TKIs has only been demonstrated in EGFRmutated lung cancer. Although they only cause minimal adverse events and can cross the blood-brain barrier to act against brain metastases (6), EGFR-TKIs have not been widely used in the clinical setting. In fact, EGFR-TKI (erlotinib) has little antitumor effect against pancreatic cancer and is rarely used in practice (7).As described in a recent study (8), lurasidone is an antagonist for D2, 5-HT 7 , and 5-HT 2A and has been used worldwide as one of the first-line therapies for depression and psychosis. It is well-tolerated in patients as it has little impact on metabolism. Since cancer is a challenging disease with a high risk of mortality, many cancer patients experience depression-like symptoms and require treatment with antidepressants (9).We have previously examined the effects of antidepressants and antipsychotic drugs, such as aripiprazole, olanzapine, and brexpiprazole, and demonstrated that they reduce the "stemness" properties of cancer stem cells and suppress drugresistance against anticancer agents (10-14). Similar to these drugs, lurasidone may have wider applications and may be welltolerated in frail cancer patients. There are also several challenges to enable the use of these agents in cancer patients; for example, olanzapine is ...

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Section: Lurasidone Sensitizes Various Tumor Cells To Osimertinib the Indicated Cancer Cells Were Cultured With Or Without 2 μM Osimertinsupporting

confidence: 89%

Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin

et al. 2021

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“…Autophagy (herewith referring to macroautophagy) consists in the p62/SQSTM1-mediated entrapment of cellular components, such as protein aggregates, membranes, and mitochondria (mitophagy) along with portions of cytoplasm, within a double-membrane organelle named autophagosome that upon fusion with the lysosome determines the degradation of those components [27]. This process is regulated by several signaling pathways and autophagy-related (ATG) proteins that also include oncogene products and tumor suppressors, which explains why this process is dysregulated in cancer [28]. Under metabolic stress conditions such as those determined by the lack of nutrients (amino acids, glucose) and of hormones and growth factors, autophagy is upregulated to provide energy and substrates from degradation of redundant self-components [29].…”

Section: Molecular and Cellular Effects Of Calorie Restriction At Glancementioning

confidence: 99%

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

et al. 2021

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Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/ or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as "Caloric Restriction Mimetics" that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo-and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.

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“…In this sense, the cell death response acts as a backup strategy for maintaining tissue homeostasis [108]. Consequently, just as with apoptosis, autophagy may exert dual roles in cancer, either encouraging tumour endurance or acting as a self-sacrifice process, aimed at preserving tissue integrity [109][110][111].…”

Section: Apoptosis-autophagy Crosstalk In Cell Death and Survival In ...mentioning

confidence: 99%

The Apoptosis Paradox in Cancer

Morana

Wood

Gregory

2022

IJMS

120

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Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)—including phagocytes and viable tumour cells—and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with “double-edged” consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.

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Autophagy Paradox of Cancer: Role, Regulation, and Duality

Cited by 35 publications

References 170 publications

Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin

Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

The Apoptosis Paradox in Cancer

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