Necrosis, and then stress induced necrosis-like cell death, but not apoptosis, should be the preferred cell death mode for chemotherapy: clearance of a few misconceptions

Abstract

Cell death overarches carcinogenesis and is a center of cancer researches, especially therapy studies. There have been many nomenclatures on cell death, but only three cell death modes are genuine, i.e. apoptosis, necrosis and stress-induced cell death (SICD). Like apoptosis, SICD is programmed. Like necrosis, SICD is a pathological event and may trigger regeneration and scar formation. Therefore, SICD has subtypes of stress-induced apoptosis-like cell death (SIaLCD) and stress-induced necrosis-like cell death (SInLCD). Whereas apoptosis removes redundant but healthy cells, SICD removes useful but ill or damaged cells. Many studies on cell death involve cancer tissues that resemble parasites in the host patients, which is a complicated system as it involves immune clearance of the alien cancer cells by the host. Cancer resembles an evolutionarily lower-level organism having a weaker apoptosis potential and poorer DNA repair mechanisms. Hence, targeting apoptosis for cancer therapy, i.e. killing via SIaLCD, will be less efficacious and more toxic. On the other hand, necrosis of cancer cells releases cellular debris and components to stimulate immune function, thus counteracting therapy-caused immune suppression and making necrosis better than SIaLCD for chemo drug development.

Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

“…For a long time, the belief was that chemotherapy was immunosuppressive by killing immune cells thus having a deleterious effect on immunity to fight the cancer (34,35). However, some chemotherapeutic agents such as taxanes (paclitaxel and docetaxel) have been demonstrated to be immunostimulatory rather than immunosuppressive against tumors, suggesting that other mechanisms than inhibition of cell division may be at play (35,36).…”

“…However, some chemotherapeutic agents such as taxanes (paclitaxel and docetaxel) have been demonstrated to be immunostimulatory rather than immunosuppressive against tumors, suggesting that other mechanisms than inhibition of cell division may be at play (35,36). In support of these experimental observations, some studies have indicated that advanced breast cancer patients responded to treatment with paclitaxel or docetaxel through an increase of interferon (IFN)-γ, IL-2, IL-6, GM-CSF cytokine levels and enhancement of natural killer (NK) and lymphokineactivated killer (LAK) cell activity in peripheral blood (37).…”

Is Type 2 Diabetes One of Such Aging Phenomena That Lack an Irreversible Structural Change?

“…Therefore, IR is unlikely to be due to certain permanent mutations in the genome. Reiterated, it is unlikely that all cells of the body have the same mutations and thus develop IR, not only because mutations occur in a random and stochastic manner but also because many cells can no longer replicate during adulthood and thus cannot fix a mutation in the genome [2,3]. For instance, in the human brain that is 2% of the bodyweight but accounts for 20% of the whole body metabolism [14,15], neurons can no longer replicate in normal adults but manifest evident IR in T2D patients.…”

“…Actually, for this reason, most classic chemotherapeutic drugs target fast-proliferating cells, and therefore many, but not all, anabolic cells are also those responsible for the common side effects of chemotherapy, including hair loss, low blood cell counts, skin itch, nausea, vomiting, diarrhea, etc. [1,2]. In many cells of the anabolic type, especially in cancer and embryotic cells, glucose is usually metabolized via a so-called glycolysis, in which one glucose molecule is converted to not only two molecules of adenosine-5'-triphosphate (ATP) to provide energy but also two molecules of pyruvate and two molecules of reduced Nicotinamide Adenine Dinucleotide (NADH) that can be used as construction materials for building new cells [32,33].…”

“…As the consequence of this chain of mutations and cellular abnormalities, these cells acquired autonomy in replication, which is the most distinctive hallmark of tumors. While some tumors remain benign, others continue developing more mutations that allow the cells to encroach into the surrounding tissue and to metastasize to distant body sites as new habitants, which are malignant states collectively referred to as "cancer" [2,3]. Because nuclear mutations are basically irreversible, cancer is basically irreversible.…”