RESUMEN
During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR. Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence. Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.
Asunto(s)
Senescencia Celular , Inhibición de Contacto , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasias/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ciclo Celular , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo Condicionados , Fibrosarcoma/metabolismo , Citometría de Flujo , Humanos , Epitelio Pigmentado de la Retina/citología , Transducción de Señal , beta-Galactosidasa/metabolismoRESUMEN
Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, ß-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exposure to hypoxia during p21 induction prevented senescent morphology and loss of regenerative potential, thus maintaining reversible quiescence so cells could restart proliferation after switching p21 off. Suppression of geroconversion was p53- and HIF-1-independent, as hypoxia also suppressed geroconversion in cells lacking functional p53 and HIF-1α. Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR pathway and suppressed senescence caused by etoposide without affecting DNA damage response, p53/p21 induction and cell cycle arrest. Also hypoxia suppressed geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE). Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused by diverse stimuli. Physiological and clinical implications of the present findings are discussed.
Asunto(s)
Senescencia Celular , Células Epiteliales/citología , Fibroblastos/citología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Etopósido/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Imidazoles/farmacología , Piperazinas/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Unfortunately, any targeted therapy is, always, started with low levels of the drug in the organism, selecting for drug resistance. One should propose that initial drug levels must be maximized, and durations may be minimized, ideally, as portions of preemptive combination of targeted drugs.
Asunto(s)
Antineoplásicos , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Neoplasias , Humanos , Resistencia a Antineoplásicos/genética , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.
RESUMEN
Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.
Asunto(s)
Acrilamidas , Compuestos de Anilina , Indoles , Neoplasias Pulmonares , Pirimidinas , Humanos , Gefitinib , Afatinib , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process.
Asunto(s)
Envejecimiento/efectos de los fármacos , Enfermedad , Rejuvenecimiento , Envejecimiento/patología , Restricción Calórica , Humanos , Longevidad/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy.
Asunto(s)
Degeneración Macular/tratamiento farmacológico , Degeneración Macular/prevención & control , Sirolimus/uso terapéutico , Animales , Coroides/efectos de los fármacos , Coroides/patología , Degeneración Macular/complicaciones , Degeneración Macular/patología , Ratones , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Proteína S6 Ribosómica/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Increasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1(+/+) versus Cav-1(-/-) age-matched young female mice). Mammary tumors grown in a Cav-1-deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging). Mammary tumors grown in a Cav-1-deficient tumor microenvironment were more than fivefold larger than tumors grown in a wild-type microenvironment. Thus, a Cav-1-deficient tumor microenvironment provides a fertile soil for breast cancer tumor growth. Interestingly, the mammary tumor-promoting effects of a Cav-1-deficient microenvironment were estrogen and progesterone independent. In this context, chemoprevention was achieved by using the mammalian target of rapamycin (mTOR) inhibitor and anti-aging drug, rapamycin. Systemic rapamycin treatment of mammary tumors grown in a Cav-1-deficient microenvironment significantly inhibited their tumor growth, decreased their stromal content, and reduced the levels of both vimentin and phospho-S6 in Cav-1-deficient cancer-associated fibroblasts. Since stromal loss of Cav-1 is a marker of a lethal tumor microenvironment in breast tumors, these high-risk patients might benefit from treatment with mTOR inhibitors, such as rapamycin or other rapamycin-related compounds (rapalogues).
Asunto(s)
Envejecimiento/fisiología , Anticarcinógenos/uso terapéutico , Caveolina 1/fisiología , Neoplasias Mamarias Animales/prevención & control , Sirolimus/uso terapéutico , Animales , Caveolina 1/deficiencia , Femenino , Neoplasias Mamarias Animales/irrigación sanguínea , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/fisiopatología , Ratones , Ratones Noqueados , Trasplante de Neoplasias , Neovascularización Patológica/metabolismo , Ovariectomía , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Transducción de Señal/fisiología , Células del Estroma/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Microambiente Tumoral/fisiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Many carcinogens are mutagens, indicating that mutagenesis is the driving force of carcinogenesis. But what if we turn this prevailing view on its head? I will argue here that carcinogens are cytostatic and/or cytotoxic, and it is not mutation per se, but clonal selection for resistance to these antiproliferative conditions, that leads to cancer. But why aren't all cytotoxins carcinogenic?
Asunto(s)
Transformación Celular Neoplásica , Antineoplásicos/uso terapéutico , Carcinógenos/toxicidad , División Celular , Predisposición Genética a la Enfermedad , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology). p53 can also cause reversible arrest without senescent morphology, which has usually been interpreted as failure of p53 to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53. Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence.
Asunto(s)
Senescencia Celular , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Humanos , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR , Activación Transcripcional , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Both individuals taking rapamycin, an anti-aging drug, and those not taking it will ultimately succumb to age-related diseases. However, the former, if administered disease-oriented dosages for a long time, may experience a delayed onset of such diseases and live longer. The goal is to delay a particular disease that is expected to be life-limiting in a particular person. Age-related diseases, quasi-programmed during development, progress at varying rates in different individuals. Rapamycin is a prophylactic anti-aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself.
Asunto(s)
Longevidad , Sirolimus , Humanos , Sirolimus/farmacología , EnvejecimientoRESUMEN
At the very moment of cell-cycle arrest, the cell is not senescent yet. For several days in cell culture, the arrested cell is acquiring a senescent phenotype. What is happening during this geroconversion? Cellular enlargement (hypertrophy) and hyperfunctions (lysosomal and hyper-secretory) are hallmarks of geroconversion.
Asunto(s)
Senescencia Celular , Puntos de Control del Ciclo Celular/genética , Senescencia Celular/genética , Proliferación CelularRESUMEN
There is no doubt that prostate cancer is a disease. Then, according to hyperfunction theory, menopause is also a disease. Like all age-related diseases, it is a natural process, but is also purely harmful, aimless and unintended by nature. But exactly because these diseases (menopause, prostate enlargement, obesity, atherosclerosis, hypertension, diabetes, presbyopia and thousands of others) are partially quasi-programmed, they can be delayed by slowing aging. Is aging a disease? Aging is a quasi-programmed disease that is partially treatable by rapamycin. On the other hand, aging is an abstraction, a sum of all quasi-programmed diseases and processes. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal.
Asunto(s)
Envejecimiento , Neoplasias de la Próstata , Humanos , Masculino , Animales , Menopausia , Sirolimus , LongevidadRESUMEN
Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
Asunto(s)
Neoplasias Pulmonares , Sirolimus , Ratones , Animales , Sirolimus/farmacología , Sirolimus/uso terapéutico , Everolimus/farmacología , Envejecimiento , Carcinógenos/farmacología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.
Asunto(s)
Antineoplásicos , Neoplasias Encefálicas , Humanos , Resistencia a Antineoplásicos , Antineoplásicos/farmacología , Caspasas , Combinación de MedicamentosRESUMEN
Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.
Asunto(s)
Uso Fuera de lo Indicado , Sirolimus , Humanos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , LongevidadRESUMEN
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Asunto(s)
Apoptosis , Caspasas , Animales , Humanos , Apoptosis/genética , Muerte Celular , Caspasas/genética , Caspasas/metabolismo , Carcinogénesis , Mamíferos/metabolismoRESUMEN
Angiogenesis is necessary for tumor growth (a rationale for antiangiogenic therapy), but hypoxia caused by such a therapy will, in theory, drive tumor progression and metastasis. To reconcile conflicting notions, we discuss that, first, although a shift from normoxia (21% O2) to hypoxia indeed activates cancer cells for aggressive behavior, this may not occur during therapy, because most cancers are not normoxic to start with. Second, only successful antiangiogenic therapy, which is capable of controlling cancer, will select for resistance and progression. After all, in order to occur, therapy-induced tumor progression must be preceded by tumor regression.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Neovascularización Patológica/metabolismo , Factores de Transcripción/metabolismo , Animales , Apoptosis/fisiología , Humanos , Hipoxia/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Making provocative headlines, three outstanding publications demonstrated that early-life treatment with rapamycin, including treatments during developmental growth, extends lifespan in animals, confirming predictions of hyperfunction theory, which views aging as a quasi-program (an unintended continuation of developmental growth) driven in part by mTOR. Despite their high theoretical importance, clinical applications of two of these studies in mice, Drosophila and Daphnia cannot be implemented in humans because that would require growth retardation started at birth. A third study demonstrated that a transient (around 20% of total lifespan in Drosophila) treatment with rapamycin early in Drosophila adult life is as effective as lifelong treatment, whereas a late-life treatment is not effective. However, previous studies in mice demonstrated that a transient late-life treatment is highly effective. Based on hyperfunction theory, this article attempts to reconcile conflicting results and suggests the optimal treatment strategy to extend human lifespan.
Asunto(s)
Envejecimiento , Sirolimus , Humanos , Ratones , Animales , Sirolimus/farmacología , Sirolimus/uso terapéutico , Longevidad , DrosophilaRESUMEN
Some visionaries prefer to dream of immortality rather than to actually live longer. Here I discuss how combining rapamycin with other modalities may let us live long enough to benefit from future discoveries in cellular reprogramming and what needs to be done at Atlos Labs to make this happen.