A Novel Therapeutic Treatment Utilizing Cordycepin and Cladribine Synergy to Decrease Adverse Treatment Effects in Various Cancer Cell Lines

Modern methods of cancer treatment like chemotherapy are effective in eradicating cancer cells; however, the following immunosuppression and cellular damage that occur are often strenuous on the human body. This study sought to design a novel therapeutic treatment model that could not only reduce adverse effects experienced by patients, but also be applied to multiple forms of cancer and their respective treatment regimes. Studies with the adenosine analog 3’-deoxyadenosine, extracted from Cordyceps sinensis, have proven its ability to induce cancer cell apoptosis through polyadenylation interference while preventing damage to healthy cells. However, Cordycepin meets intrinsic resistance in the body from adenosine deaminase (ADA). Therefore, Cordycepin coupled with an ADA inhibitor can potentially form a novel therapy that expresses a decrease in cytotoxicity toward healthy cells. The chemo-drug/ ADA inhibitor Cladribine (2-chlorodeoxyadenosine), a synthetic analog of 3’-deoxyadenosine, used in synergy was hypothesized to work in two ways: 1) Cladribine, as an ADA inhibitor, induces synergism in its apoptotic anti-cancer effect on cancer cells, and 2) the enhanced efficacy of the combined treatment allows for the reduction of the toxic chemo-drug, alleviating Cladribine’s toxicity on healthy cells while maintaining treatment efficacy. The novel treatment was assessed through cell proliferation assays, morphological observation, and confirmed through flow cytometric analysis. Results indicated that Cordycepin/ Cladribine synergy experienced similar levels of cancer cell inhibition as Cladribine alone, but exhibited a significant increase in healthy cells left unharmed. The combined treatment also effectively models the potential to expand Cordycepin to additional chemo-drugs/ADA inhibitors and better patient outlooks for respective treatments. Introduction Traditionally to combat cancer, most patients receive chemotherapy, radiation, and/or surgery to reduce cancerous tumor cells. However, these methods involve destroying healthy cells and lead to plethora of side effects including immunosuppression, myelosuppression, and gastrointestinal distress1. The purpose of this study in its entirety was to research and develop a novel cancer therapy that could potentially reduce toxic treatment side A Novel Therapeutic Treatment Utilizing Cordycepin and Cladribine Synergy to Decrease Adverse Treatment Effects in Various Cancer Cell Lines Jason Cui1*, Robert Culbertson2, Zebin Mao3, and Beverly Mock4 Student1, Teacher2: Langley High School, 6520 Georgetown Pike, McLean, VA 22101 Mentor3: Peking University School of Basic Medical Sciences, 38 Xue Yuan Road, Beijing, China Mentor4: National Institutes of Health, 37 Convent Drive, MSC4258, Bethesda, MD 20892-4258 *Corresponding author: [email protected] INTERNSHIP ARTICLE effects to healthy cells without sacrificing treatment efficacy. Cordyceps sinensis is a species of endoparasitical fungi of the genus Cordyceps, also referred to as the Chinese Caterpillar Fungus, or “Dong Chong Xia Cao”2. As its name suggests, Cordyceps sinensis is a fungus, but what differentiates it from the latter is its unique way of imbedding itself on a host tissue. Caterpillar fungi are the result of a parasitical relationship between the larva of the ghost moth and the fungus, both of which are located in the Tibetan plateau. The fungus imbeds itself into and mummifies the larva, and then grows from the body insect. Cordyceps sinensis has had an extremely long history of use, the first by the Chinese Qing Dynasty dating back to 1757 AD. The documented uses back then were as lung and kidney supplements to improve health. However, the caterpillar fungus has now been called an overall tonic that can “improve the general well being of a human”3. Cordyceps sinensis has been acknowledged to treat a wide variety of conditions like respiration problems, pulmonary diseases, renal, liver, and cardiovascular diseases, low sex drive, and immune disorders4. It is also considered to be a remedy for fatigue, being used by multiple athletes in the 2008 Summer Olympic Games. Studies have also shown that Cordyceps sinensis is able to increase cellular ATP levels3. Recent research, however, has investigated the possible antitumor or anti-cancer ability of Cordyceps sinensis with the basis that it can prove to be a therapeutic alternative to traditional methods of treatment. Studies have been done with mice that have cervical cell carcinoma and Lewis lung cancer in which extracts from Cordyceps sinensis were added to mice showed significant reductions in tumor size5. In a different experiment, extracts from the genus Cordyceps was applied in a dose of 0.5 mg/kg to a mouse with a resulting tumor inhibition rate of 98.7%6. It has been found that the key factor contributing to Cordyceps sinensis’ anti-cancer ability is a chemical compound found in Cordyceps sinensis called Cordycepin. Cordycepin (3’-deoxyadenosine) is a nucleoside analog and a derivative of the nucleoside adenosine, differing from the latter by the absence of oxygen in its 3’-position2. Cordycepin is a known polyadenylation inhibitor with a large spectrum of biological activities, including anti-proliferative, pro-apoptotic and antiinflammatory effects2. Polyadenylation is a necessary step for the synthesis and maintenance of functional RNA transcripts catalyzed by poly(A) polymerase. Polyadenylation involves the