Current Challenges to Find the Right Cancer Treatment

Since there are multiple possible factors which drive transformation of normal cells to become malignant cancer cells, prevention remains very difficult and eradication of cancer once it is already established still poses myriad challenges. Conventional cancer therapy, including chemotherapy and radiation therapy, primarily targets actively proliferating cells. 

Chemotherapeutic drugs do not differentiate between actively dividing normal cells and cancer cells. Therefore, severe toxic effects are observed in patients due to inadvertent but unavoidable loss of normal cells. This results in neurotoxicity, cardiotoxicity, gastrointestinal toxicity, and immune suppression. Furthermore, chemotherapeutic drugs are often associated with resistance.^3,4

Therefore, many cancer patients whose disease recurs after a brief remission are in dire need of alternative medicines that also address other cancer hallmarks and cause less toxicity.

Metabolic Reprogramming: The Key Reason Why Existing Cancer Therapies Fail

Glucose is the main energy source for normal, eukaryotic, non-cancer cells. During glucose metabolism, normal cells produce CO₂ via oxidative phosphorylation under aerobic conditions or lactate via glycolysis under anaerobic conditions. In cancer cells, the metabolic shift towards excessive glucose consumption—over 200 times the normal rate, known as aerobic glycolysis or the Warburg effect—plays a pivotal role.^5,6

Unlike in normal tissues, where cells only exhibit glycolysis under oxygen-limited or anerobic conditions, cancer cells reprogram the metabolic pathway to carry out glycolysis even in aerobic conditions to meet the high energy demand of uncontrolled cell division; this is called the Warburg effect or aerobic glycolysis and is a critical trait that distinguishes cancer cells from normal cells.

This metabolic alteration leads to an overproduction of lactate, which is then expelled from the cells. This expulsion leads to lactic acid accumulation, which promotes acidification of the tumor microenvironment, a condition that can suppress the immune system and potentially reduce the efficacy of certain immunotherapy treatments.

Why Are Low Sugar/Ketogenic Diets Ineffective?

Furthermore, strategies like ketogenic diets or sugar avoidance are generally ineffective in this context. These approaches often accelerate cachexia, a severe form of muscle and weight loss, hastening the progression to mortality.⁷

This ineffectiveness is primarily because cancer cells are adept at extracting essential nutrients from muscles (notably glutamine) and other tissues for their sustenance, thereby undermining the intended impact of dietary restrictions.

Repurposing Non-Cancer Drugs to Fight Cancer

The development of new anti-cancer drugs is becoming increasingly difficult and cost prohibitive. To find an effective therapeutic cure for cancer, drugs that are already clinically approved or experimentally tested for conditions other than cancer, but are found to possess previously unrecognized cytotoxicity towards malignant cells are proving to be very useful.

Cancer researchers have identified certain drug molecules which could serve as fitting anti-cancer candidates alongside conventional therapies. Therefore, repurposing drugs with anti-cancer efficacy can be considered an important strategy for cancer therapy today.⁸

Because of the above outlined mechanism of metabolic reprogramming by which standard cancer therapies typically fail, it would make the most sense to focus on repurposed drug candidates that combat this very mechanism.

Thus, while many promising drug candidates exist to complement existing anti-cancer therapies, there is strong rationale to focus on those drugs that overcome one specific hallmark of cancer in particular: metabolic reprogramming.

Drugs That Help Overcome Metabolic Reprogramming in Cancer: Fenbendazole, Sodium dichloroacetate (DCA) and 2-deoxy-d-glucose (2-DG)

   a) How the 3 drugs have unique, independent and synergistic mechanisms to combat excessive glucose consumption in cancer cells:

      i. Fenbendazole – reduces GLUT transporters and affects hexokinase 2

Fenbendazole (FBZ) (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a class of benzimidazole drugs, which finds usage as an anti-cancer drug. FBZ has proven anticancer effect as it arrests cell proliferation, lowers glucose uptake and triggers apoptotic cell death.^{9 ,10,11}  

Repurposing of Fenbendazole is hence an important option in cancer therapy that can reduce considerable time and cost required to develop new drugs.

Cancer is associated with a metabolic disorder wherein the cancer cells selectively prefer inefficient aerobic glycolysis (which generates only 2 molecules of ATP) over mitochondrial oxidative phosphorylation (which generates 38 molecules of ATP) to meet their energy needs. Aerobic Glycolysis is an energy inefficient process, so the cancer cells’ need to increase their glucose consumption by several folds.

Cancer cells increase uptake of glucose by upregulating GLUT1, a membrane protein which facilitates basal uptake of glucose. FBZ treatment results in reduced glucose uptake in cancer cells due to downregulation of GLUT transporters and other key glycolytic enzymes like Hexokinase II (HKII).

In order to drive aerobic glycolysis, many glycolytic enzymes are upregulated during tumorigenesis. Hexokinase II (HKII), a key glycolytic enzyme, plays a critical role in glucose retention and metabolism by phosphorylating glucose to glucose-6-phosphate, which can then enter glycolysis.

HKII is thus a highly advantageous enzyme for cancer cell survival and proliferation. FBZ impairs the enzymatic function of HKII in cancer cells leading to reduced glucose retention in FBZ treated cells, eventually the cancer cells die because they cannot utilize glucose as an energy source via aerobic glycolysis.¹¹