Chemoresistance remains a lethal challenge in the realm of cancer biology and clinics. Various determinants with their modes of action have been reported with clinical implications. However, many patients regrettably die due to chemoresistance-induced failure in treatment.
Cancer is one of the major causes of death globally, accounting for 10 million deaths in 2020 . The most common cancers and those responsible for deaths reported in 2020 in both men and women are shown in Figure 1, which highlights a major concern regarding the number of humans affected by cancer worldwide.
Surgery, hormone therapy, gene therapy, immunotherapy, radiation therapy, laser therapy, combination therapy, and targeted therapy are the major cancer treatments available, with chemotherapy being the most common and promising treatment for cancer management . Despite the progress made in cancer treatment, resistance to chemotherapeutic drugs continues to be a major problem in cancer therapy ( Figure 2 ) and is responsible for most relapses and poor survival outcomes in patients.
The resistance to the chemotherapeutic regimens has been reported for almost all the drugs used to treat the most lethal cancers. The resistance to doxorubicin , paclitaxel , 5-fluorouracil , cyclophosphamide  and carboplatin  have been shown to cause cancer recurrence in breast cancer associated with poorer prognosis and shorter survival. Resistance to 5-fluorouracil , cisplatin , docetaxel  and oxaliplatin  result in the same outcomes in gastric cancer patients. Moreover, the resistance to 5-fluorouracil , irinotecan , and oxaliplatin  in colorectal cancer, cisplatin , carboplatin , paclitaxel 23] and docetaxel  in lung, and gemcitabine , oxaliplatin , cisplatin  and doxorubicin  strongly indicate that the chemoresistance phenomenon intensively threatens the health and survival of cancer patients. Approximately 80–90% of mortality in cancer patients is directly or indirectly attributed to drug resistance . Resistance can be restricted to a specific drug, or different drugs with independent modes of action, named multidrug resistance (MDR).
The effectiveness of chemotherapeutic drugs depends on their successful entry into the cells at an optimum intracellular concentration. Drug influx is affected by the location of the tumor within the body, size of the tumor, physics of the tumor site, the structure and function of the tumor vasculature, necrosis of the tumor, transport properties of the drug as it moves through microvessel walls and in the extravascular tissue, alterations in binding properties and number of drug uptake transport systems (influx pumps), mode of drug diffusion, and absorption of the drug and intracellular pH .
EMT is the process by which epithelial cells acquire a mesenchymal phenotype. They lose cell polarity and cell-to-cell adhesion and gain migratory and invasive properties, thus promoting metastasis. EMT is related to cancer progression, metastasis and mediates drug resistance to chemotherapy. Several factors like reduced expression of epithelial markers E-cadherin and occludin and increased expression of mesenchymal markers vimentin, fibronectin and N-cadherin, tumor microenvironment, hypoxia and signal transduction pathways (WNT, Notch, Hedgehog) can trigger EMT, leading to drug resistance . EMT-inducing transcriptional factors (EMT-TFs) play a role in drug resistance. Overexpression of EMT-TFs like Twist, Snail, Slug, Zinc finger E-box binding homeobox 1 (ZEB1) and Forkhead box C2 (FOXC2) are known to induce drug resistance in breast cancer . ZEB1 induces EMT by suppressing the epithelial phenotype by repressing epithelial microRNAs such as miRNA-200 family members . Some of the EMT-TFs promote resistance by enhancing drug efflux by ABC transporters. Overexpression of ATP-binding cassette C5 transporter (ABCC5) correlates with Forkhead box M1 (FOXM1) in paclitaxel-resistant nasopharyngeal carcinoma cells. Down-regulation of FOXM1 or ABCC5 reduces drug efflux and leads to cell death by paclitaxel .
Anticancer drugs require metabolic activation, and thus cancer cells can develop resistance through drug inactivation or reduced drug activation. Drug activation and inactivation are seen in the glutathione S-transferase (GST) superfamily, a group of detoxifying enzymes that catalyze the conjugation of glutathione (GSH) to electrophilic compounds. GST enzymes induce drug resistance through direct detoxification of cancer drugs or by inhibiting the MAPK pathway . Another mode of drug inactivation occurs through the cytochrome P450 (CYP) system. The CYP system consists of two classes. Class I includes enzymes CYP1A1, CYP1A2, CYP2E1, and CYP3A4, which are involved in the metabolism of drugs and procarcinogens. Class II consists of the enzymes CYP2B6, CYP2C9, CYP2C19, and CYP2D6, which are involved in drug metabolism. It is suggested that mutations in these enzymes would result in the breakdown and secretion of the drugs, thus reducing their optimum concentration leading to drug resistance . CYP450 class I metabolizing enzymes are shown to inactivate the drug Irinotecan, a topoisomerase I inhibitor used for colon cancer treatment . The DNA-binding glycopeptide drug bleomycin is inactivated by bleomycin hydrolase. Cancers resistant to bleomycin have high levels of this enzyme, whereas sensitive tumors (germ cell cancers, lymphomas, squamous carcinomas) have low levels .
Inducing DNA damage is one of the modes of action of chemotherapeutic drugs to kill cancer cells. If the cells are able to repair the DNA damage caused, they will escape cell death and will develop chemoresistance. DNA damage response (DDR) mechanisms can reverse the drug-induced damage.
High-throughput pharmacogenomics and CRISPR screens are being used to investigate populations of cancer cells carrying sensitivity biomarkers and unexpectedly resistant (UNRES) cell lines for unique genetic alterations that may drive resistance. In one study, genomics of drug sensitivity in cancer (GDSC) and clinical trials reporting program (CTRP) datasets were analyzed to find UNRES cases and identify putative resistance biomarkers. Interrogating the foundations of drug resistance with publicly available CRISPR phenotypic assays assists in ranking resistance drivers and offering hypotheses for drug combinations . The EGFR T790M mutation and PTEN loss in lung adenocarcinoma cells treated with EGFR inhibitors have been proposed as the resistance biomarkers based on their hypothesis.
Natural products with their diverse chemical structures and pharmacological benefits can serve as substrates to treat drug resistance. Natural products do so by two approaches. The first is they reduce drug efflux and thus maintain optimum concentration of the drug. The P-gp transporter protein is responsible for efflux of cancer drugs. Binding of P-gp to the drug results in activation of its ATP-binding domain and hydrolysis of ATP causing a change in the shape of P-pg, leading to drug efflux. Natural products that can inhibit the action of the P-gp transport system are being developed. For example, tanshinone microemulsion can significantly reverse drug resistance of K562/ADM cells by inhibiting the P-gp efflux pump effect and increasing the intracellular concentration of chemotherapeutic drugs. Other natural products effective in combating drug resistance include tetrandrine, quercetin, grape-seed polyphenols, and tea polyphenol .
The second approach is they induce non-apoptotic cell death in cancer cells. Natural products induce non-apoptotic cell death processes like necroptosis (Shikonin and its analogs, MAM), autophagy (Arsenic trioxide, G. lucidum triterpene, resveratrol, oridonin, allicin), methuosis (chalcone; ginsenoside; curcumin; quercetin) and oncosis (sanguinarine, solamargine, artesunate, rosin) in cancer cells overcoming chemoresistance .
Fourteen single compounds shown to be able to overcome cancer cell drug resistance are evodiamine, peiminine, isorhynchophylline, berberine, ephedrine, ginsenoside Rb1, oridonin, oxymatrine, methylether-scutellarein, sodium norcantharidate, phenyl-propanoid glycoside, retinoic acid, schizandrin A, and baicalin . There exists an inverse correlation between consumption of dietary polyphenols and the risk of cancer. Polyphenols possess antioxidant capacity and inhibit activation of procarcinogens, cancer cell proliferation, metastasis, angiogenesis and drug efflux transporters. They also induce apoptosis in cancer cells and modulate immune responses and inflammatory cascades .