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Rahman, M.H.; Cavalu, S.; Karthika, C.; Sureshkumar, R.; Zehravi, M.; Akter, R.; Ali, F.; Ramproshad, S.; , .; Dey, A.; et al. Possible Strategy for Colon Carcinoma Cells. Encyclopedia. Available online: https://encyclopedia.pub/entry/23759 (accessed on 25 December 2025).
Rahman MH, Cavalu S, Karthika C, Sureshkumar R, Zehravi M, Akter R, et al. Possible Strategy for Colon Carcinoma Cells. Encyclopedia. Available at: https://encyclopedia.pub/entry/23759. Accessed December 25, 2025.
Rahman, Md. Habibur, Simona Cavalu, Chenmala Karthika, Raman Sureshkumar, Mehrukh Zehravi, Rokeya Akter, Faraat Ali, Sarker Ramproshad,  , Abhijit Dey, et al. "Possible Strategy for Colon Carcinoma Cells" Encyclopedia, https://encyclopedia.pub/entry/23759 (accessed December 25, 2025).
Rahman, M.H., Cavalu, S., Karthika, C., Sureshkumar, R., Zehravi, M., Akter, R., Ali, F., Ramproshad, S., , ., Dey, A., & Antonescu, A. (2022, June 07). Possible Strategy for Colon Carcinoma Cells. In Encyclopedia. https://encyclopedia.pub/entry/23759
Rahman, Md. Habibur, et al. "Possible Strategy for Colon Carcinoma Cells." Encyclopedia. Web. 07 June, 2022.
Possible Strategy for Colon Carcinoma Cells
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This entry is adapted from the peer-reviewed paper 10.3390/life12060811

Cancer is a major cause of mortality globally. The major reasons for the failure of cancer treatment is the late diagnosis of cancer and multidrug resistance. Colorectal cancer is the world’s third most common cancer. The desire for fast food has increased the risk of colon cancer in the modern era. Because of the various side effects of treatment methods, such as alopecia, gastrointestinal tract irritation, and the possibility of secondary cancer (leukemia), a novel approach to reducing potential side effects became critical. The combination of flavonoids and chemotherapeutic agents offers a safe and effective therapeutic criterion that can address the issues associated with therapy failure while also producing a synergistic effect. 

cancer colon cancer 5-fluorouracil

1. Introduction

When colorectal cancer is detected in its early stages, surgery is the most commonly used treatment [1]. Surgery does not treat the disease; it only relieves the symptoms. Colectomy is performed to eradicate the cancerous portion of the colon, but it can lead to significant clots, blood loss, and infections. Patients may experience swelling, severe pain, and unpredictable emotional or physical stress responses as a result of the treatment methods [2]. Radiotherapy is an additional treatment option that uses advanced radiation energy to kill cancerous cells. It can cause rectal irritation, painful bowel movements, and blood in the stool in some patients [3].
Chemotherapy is a treatment that kills abnormal cells by using chemicals or drug substances. It is mostly used before and after surgery because it shrinks tumor cells and lowers the likelihood of recurrence. Colorectal cancer medications include 5-fluorourcil (5-FU), irinotecan, capecitabine, oxaliplatin, cetuximab, bevacizumab, panitumumab, regorafenib, and others. Chemotherapy attacks drug-sensitive cells while leaving drug-resistant cells alone; however, when tumor cells re-grow, chemotherapy fails because the cells become resistant to the medication. Another reason for chemotherapy failure is the multidrug resistance produced by cancer cells to a wide range of anticancer drugs [4]. The overexpression of P-glycoprotein prevents chemotherapy drugs from entering cancer cells, posing a barrier to treatment success, eventually leading to multidrug resistance. Most cancer cells have become drug-resistant, necessitating the development of a new strategy to overcome this resistance and ensure the success of the therapy [5].
Flavonoids are the most common polyphenolic compound in the human diet, along with the secondary metabolites originating in both plants and animals [6]. Its anticancer action and natural P-gp inhibitory activity have been described in numerous surveys and studies. Because they have anticancer activity, it is thought that when combined with 5-fluorouracil, they have synergistic effects in the human body. The multi-use of lipids provides several advantages, including improved bioavailability, drug targeting to tumor cells, the lymphatic targeting of the drug, which has benefits during the metastatic stage, and abridged toxicity [7].

2. Outline and the Hypothetic Concept

5-FU, the first-line treatment regimen for colorectal cancer, has caused cancer cells to develop resistance. This is one of the primary reasons for the therapy’s failure. Curcumin, a naturally occurring flavonoid, has been shown in numerous studies to have anti-cancer and MDR inhibition properties [8]. Furthermore, flavonoids are well known for their immunomodulatory, antioxidant, anti-inflammatory, and antimicrobial properties, among others. These findings support the hypothesis that flavonoids can be used to enhance the activity of first-line therapy as an antiproliferative agent [9]. Curcumin and 5-FU together have the potential to recover the potency and efficacy of cancer treatment. A significant amount of research suggests curcumin’s chemosensitizing property, which gives it an advantage in addressing this issue. Because lipid-based drug delivery travels through the lymphatic system, including lipids in this combination [10] can help with cancer cell targeting and even treatment during the metastatic stage [11]. As a result, this novel combination has the potential to overcome the issues related to therapy failure and serve as an alternative throughout the metastatic phase of cancer. Because cancer cells spread through the lymphatic system from the site of formation, targeting the lymphatic system may aid in disease suppression. As a result, the treatment mode’s efficacy can be improved [12]. Furthermore, lipid-based nano systems help to suppress P-gp efflux transporters, which helps to reverse MDR-related issues [13].

3. Hypothetical Approaches

A novel method for targeting colorectal cancer cells that employs a dual combination of flavonoids and chemotherapeutic drugs is discussed below. The concept stated above can be tested experimentally. The most difficult challenge in colorectal cancer treatment is multidrug resistance (MDR). P-gp is the main reason for MDR in cancer cells [14]. MDR is a situation in which cancer cells efflux drugs, as well as other foreign bodies, resulting in lower absorption of the drug inside the cells and ineffective treatment. Flavonoids have also been shown to be effective as chemosensitizers, which can influence drug efficacy [15]. In addition to the aforementioned issues, the causes of therapy failure include rapid drug catabolism, poor absorption, and short biological half-life, all of which can be avoided by converting to lipid drug conjugates in lipid-based drug delivery systems [16]. P-gp is expressed in the intestine and reduces drug absorption as a substrate; it therefore plays an important role in regulating drug distribution and bioavailability. As a result, the drug’s bioavailability and therapeutic plasma concentration do not occur [17]. However, lowering P-gp expression allows the drug to influence therapeutic plasma concentrations. The substrate is transported to P-gp via a cytoplasmic opening or an entrance in the membrane’s inner leaflet [18]. The cytoplasmic side of the protein binds ATP (adenosine triphosphate). The substrate that must be eliminated from the cell changes because of ATP hydrolysis. The substrate is expelled when phosphate is liberated from the initial ATP molecule [19]. A new ATP molecule attaches to the secondary ATP binding site when an adenosine diphosphate (ADP) is released. If the protein is reactivated by hydrolysis and the release of ADP and a phosphate molecule, the process restarts [20]. P-gp activity is inhibited by curcumin.
Curcumin is a flavonoid that occurs naturally and is widely consumed [8]. Flavonoids are absorbed by intestinal cells after passing through the digestive tract. Several studies have shown that flavonoids can kill cancer cells and prevent their growth. The inhibition of enzymes, DNA, and proteins is specifically targeted. Natural inhibitors have a greater potential impact on safety, efficacy, and cost than chemical or synthetic inhibitors [21]. The synergistic effect of flavonoids can overcome the limitations on most anticancer medications caused by multidrug resistance [22].
Curcumin has also been shown to be effective at preventing P-gp-induced MDR [23]. It inhibits P-gp via the P13K/Akt/NF-kB pathway in mouse MDR leukemia L1210 cells, according to studies. When adriamycin and curcumin were combined, the Western blotting results showed that it could cleave PARP inhibitors and overcome P-gp-induced MDR. Curcumin has previously been shown, in animal studies and cell culture assays, to have anti-cancer properties [24]. Curcumin inhibits lipoxygenase activity and the production of cyclooxygenase 2. It prevents carcinogenesis from occurring by suppressing the cytochrome P-450 enzyme and increasing glutathione-S-transferase levels. It inhibits the promotion and progression of carcinogenesis while also influencing the formation of colon cancer cells with DNA mismatch repair defects [25]. As a result, curcumin may be a safe chemotherapeutic drug for tumors with DNA mismatch repair failure and microsatellite instability [26].
Lipid drug conjugates can help this approach in several ways. LDCs are lipids that have been conjugated to the parent medication either covalently or non-covalently. The drug’s lipophilicity and other characteristics are enhanced by conjugation with the lipid. This approach facilitates the distribution of medicine to the desired location. This section explains how to work with lipids produced from fatty acids. A drug molecule can enter the triglyceride (TG) deacylation–deacylation pathway when one of the fatty acids is replaced with a drug molecule. TG hydrolyzes into 2-monoglyceride (2-MG) and free fatty acid in the gastrointestinal lumen, where it is absorbed by erythrocytes and deacylated back to TG. Subsequently, the TG is converted into lipoprotein and stored in the lymphatic system [27]. These drug conjugates use lymphatic transport to improve medication absorption and target lymphatic drugs. Ex vivo testing can be used to investigate this by categorizing, locating, and isolating lymph nodes, as well as extracting the medicine to determine the drug concentration in the lymphatic system. The lymphatic system’s function in transporting dietary lipids from the intestine to the lymphatic capillaries allows the lipid drug mixture to efficiently use this pathway, integrate into the enterocytes, and arrive in the lymphatic capillaries, thereby overcoming the first-pass metabolism observed during oral drug administration [28].
This approach has the potential to treat metastatic malignancy because metastasis occurs primarily through the lymph nodes. Cancer cells use and metabolize more lipids than normal cells to proliferate rapidly. Fatty acids are primarily used as a basis of energy and as predecessors in a variety of biological processes. This lipophilic prodrug cleaves the lipids, leaving the parent drug behind, and is then delivered to tumor cells, causing cytotoxicity [29]. The mechanism of action of conjugates is depicted schematically in Figure 1. When it comes to delivering anticancer drugs to affected cells, nanomaterials have a high degree of selectivity and specificity. This combination has the potential to increase the cytotoxicity in colon cancer cells while leaving normal cells alone. This method can be accepted by the tumor microenvironment by improving retention and permeation (EPR). Flavonoids may have clinical applications through their inhibition of P-gp and, thus, their reversal of neoplastic MDR. Furthermore, they have the potential to produce synergistic effects. The combination of flavonoids, lipids, and chemotherapeutic drugs may be an effective treatment for colon cancer cells. Because of a lack of proper exercise and to the additional risks associated with the Western diet, the risk of colorectal cancer has increased in the modern era. As a result, this combination therapy involving lipids, flavonoids, and chemotherapeutic drugs, provides a foundation for reducing the main complications related to current therapies to some degree, in a cost-effective manner.
Figure 1. The mechanism of 5-FU lipid curcumin conjugates for the treatment of colon cancer.
The ability of drugs to target the colon is a significant phenomenon in the treatment of colorectal cancer. In this case, pectin is used as a transporter for colon-specific drug delivery. The pectinase enzyme, which is produced by anaerobic bacteria in the colon, initiates the mechanism. Other pectin properties, such as film formation and pH sensitivity, make pectin-based drug delivery systems dependable and reproducible for colon-specific drug delivery [30]. To determine the fate of the lipid and allow the release of the drug conjugate, an in vitro lipolysis medium is developed. The medium’s calcium and bile aid in the digestion of lipids (lipolysis). This model can be used to study drug release due to bond dissociation [31]. To advance pharmacokinetic research and drug delivery, the mechanism of drug transport must be studied. The delivery of the drug conjugate through the oral route and the dissociation concept are given in Figure 2.
Figure 2. The delivery of drug conjugate through oral route and dissociation concept.
Because P-gp inhibits drug absorption, distribution, and elimination, the novel method’s invasion is required for effective drug delivery to the target area. P-gp is found on the biliary canalicular surfaces of hepatocytes, the luminal surfaces of jejunum and colon cells, the apical surfaces of the proximal tubular cells of the kidney, the endothelial cells of the blood–brain barrier, the apical membrane of the fetal membrane barrier function in the placenta, and other tissues, such as the adrenals, prostate, spleen, lungs, skin, heart, and skeletal muscles [32]. To study the efflux mechanism complex in drug resistance, MDR1 Madin Darby canine kidney (MDR1-MDCK), MDCK, and carcinoma cell lines can be used (Caco2). Comparisons of cell lines are drawn to achieve better outcomes.

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Md. Habibur Rahman , SIMONA CAVALU , Chenmala Karthika , Raman Sureshkumar , Mehrukh Zehravi , Rokeya Akter , Faraat Ali , Sarker Ramproshad ,
, Abhijit Dey , Angela Antonescu
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Revisions: 2 times (View History)
Update Date: 07 Jun 2022
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