I was sent articles by two non-cancer researchers last week – they are quite fitting for discuss on this blog (thank you, Gina and Sherilyn). The first was on DCA (dichloroacetate), a drug approved for congenital lactic acidosis, and the second about bromelain, an enzyme in pineapples.
What is DCA?
Dichloroacetate is a chemical that is structurally similar to acetic acid in which two of the three hydrogen atoms have been replaced by chlorine atoms. DCA inhibits pyruvate dehydrogenase kinase, a key enzyme in glucose metabolism, which converts pyruvate to acetic acid, thereby enabling the Krebs Cycle of oxidative metabolism of glucose. Cancer cells prefer anaerobic metabolism, that is why they breakdown increased quantities of glucose (Warburg Effect); the intermediates are important for building cellular components.
By blocking pyruvate dehydrogenase kinase, DCA induces cancer cells into aerobic metabolism in the mitochondria. Since cancers are typically deprived of oxygen relative to normal tissue, aerobic metabolism is stalled for lack of oxygen and apoptosis is induced.
Why the interest in DCA?
A clinical study of patients with glioblastoma revealed potential activity of DCA on mitochondria, as well as some interesting clinical findings in 5 patients treated with DCA – Michelakis 2010. The study was not randomized, and temozolamide and radiation was concomitantly administered, so it was not possible to discern the direct effect of DCA.
The mechanism of action of DCA and early clinical results combine to generate great interest in DCA, which is a compound that is readily available commercially to treat an inborn error of metabolism.
A randomized Phase 2 clinical study of DCA versus placebo in patients with head and neck cancer who were receiving cisplatin is underway. The study is no longer recruiting and should be completed in January of 2019. [See Study of DCA (Dichloroacetate) in Combination With Cisplatin and Definitive Radiation in Head and Neck Carcinoma.]
Pineapple enzymes versus 5-fluoro-uracil
Bromelain is an extract or proteolytic enzymes from pineapples (Ananas comosus). It is used in debriding skin in the treatment of burns and as a supplement to aid in digestion of proteins. Bromelain is also used for reducing swelling (inflammation), especially of the nose and sinuses, after surgery or injury. A Phase 2 clinical study of two doses of bromelain (10mg and 50mg) is ongoing in patients with advanced stage mixed types of carcinoma of breast, lung, colon, gastro-intestinal, ovarian, cervical, uterine, prostatic, bladder, hepatic, lymphoma, and melanoma. [See Bromelain, Comosain as a New Drug for Treating and Preventing Various Types of Cancer in the Humans.]
The use of bromelain in cancer has its roots in a laboratory study of several tumor cell lines – P-388 leukemia, sarcoma (S-37), Ehrlich ascitic tumor (EAT), Lewis lung carcinoma (LLC), MB-F10 melanoma and ADC-755 mammary adenocarcinoma – along with 5-fluorouracil, a cancer drug that has been inuse for decades:
Intraperitoneal administration of bromelain (1, 12.5, 25 mg/kg), began 24 h after tumor cell inoculation in experiments in which 5-fluorouracil (5-FU, 20 mg/kg) was used as positive control. The antitumoral activity was assessed by the survival increase (% survival index) following various treatments. With the exception of MB-F10 melanoma, all other tumor-bearing animals had a significantly increased survival index after bromelain treatment. The largest increase approximately 318 %) was attained in mice bearing EAT ascites and receiving 12.5 mg/kg of bromelain. This antitumoral effect was superior to that of 5-FU, whose survival index was approximately 263 %, relative to the untreated control. Bromelain significantly reduced the number of lung metastasis induced by LLC transplantation, as observed with 5-FU. The antitumoral activity of bromelain against S-37 and EAT, which are tumor models sensitive to immune system mediators, and the unchanged tumor progression in the metastatic model suggests that the antimetastatic action results from a mechanism independent of the primary antitumoral effect.
How does bromelain work?
Studies does in mice showed that bromelain induced apoptosis-related proteins along with inhibition of NF-kappaB-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced skin tumors.